Physiological actions of taurine.

PHYSIOLOGICAL REVIEWS

Vol. 72, No. 1, January Printed

1992

in U.S.A.

Physiological

Actions of Taurine

R. J. HUXTABLE Department

of Pharmacology,

University

of Arizona

College of Medicine,

I. Introduction .......................................................................................... II. Physicochemical Considerations ..................................................................... III. Biochemical Considerations .......................................................................... A. Distribution of taurine ........................................................................... B. Metabolism of taurine ............................................................................ IV. Nonmetabolic Actions of Taurine .................................................................... A. Osmoregulation ................................................................................... B. Calcium modulation .............................................................................. C. Phospholipid interactions ........................................................................ D. Protein interactions .............................................................................. E. Interactions with zinc ............................................................................ V. Metabolic Actions: Taurine as Product .............................................................. A. Antioxidation: hypotaurine story ................................................................. B. Radioprotection ................................................................................... C. Cysteine detoxification ............................................................................ VI. Metabolic Actions: Taurine as Precursor ............................................................ A. Antioxidation: chloramine story .................................................................. B. Radioprotection by taurine ....................................................................... C. Energy storage (phosphagen) .................................................................... D. Metabolism and energy production ............................................................... E. Surfactant and detergent actions ................................................................ F. Xenobiotic conjugation ........................................................................... G. Isethionic acid and anion balance ................................................................ H. Taurine-containing peptides ...................................................................... I. Other taurine metabolites ........................................................................ VII. Conclusions ...........................................................................................

I. INTRODUCTION

Z-Aminoethane sulfonic acid, or taurine, is a phylogenetically ancient compound with a disjunct distribution in the biosphere. It is present in high concentration in algae (159, 649, 748) and in the animal kingdom, including insects and arthropods, but is generally absent or present in traces in the bacterial and plant kingdoms. In many animals, including mammals, it is one of the most abundant of the low-molecular-weight organic constituents. A 70-kg human contains up to 70 g of taurine. One is not tumbling into the abyss of teleology in thinking that a compound conserved so strongly and present in such high amounts is exhibiting functions that are advantageous to the life forms containing it. As the phylogenetic tree is ascended, substances tend to accrete functions. The adaptive advantages provided by serotonin in bananas (Muss sapienturn), norepinephrine in Solarium, and dopamine in the giant saguaro cactus (Cereus giganteus) are extended to additional phenomena when these same compounds are found in the mammalian brain. The presence of y-aminobutyric acid (GABA) in the brains of higher animals 0031-9333/92 $2.00 Copyright 0 1992 the American Physiological

Tucson, Arizona

101 102 104 104 107 108 108 114 119 123 129 130 130 133 134 135 135 136 136 138 139 141 141 142 142 142

carries a functional significance above and beyond the presence of GABA in bacteria. The osmoregulatory actions of GABA in the latter species are superseded by its neurotransmitter function in the former. A moment’s thought will multiply these examples. Thus it can be readily deduced that, in considering the physiological significance of taurine, it, in all likelihood, will exhibit polyvalent functions. Taurine was so named because it was first isolated from the bile of the ox, Bos taurus (134). The modern era of research on taurine may be considered to have been introduced by the seminal and thorough review of Jacobsen and Smith (338), which appeared in this journal in 1968. At that time, the functions suggested for taurine were limited to bile salt synthesis, osmoregulation in marine invertebrates, energy storage in marine worms, and neuroinhibition in the central nervous system (CNS). Since then, the increase in the range of phenomena with which taurine has been associated has been little short of astounding. Phenomena currently associated with taurine are listed in Table 1. The purpose of this review is not to examine these phenomena per se but to elucidate the mechanisms by which taurine

Society

101

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102 TABLE

R. J. HUXTABLE

Volume

72

1. Some biological actions of taurine Action

References

Cardiovascular

Antiarrhythmic Positive inotropy at low calcium Negative inotropy at high calcium Potentiation of digitalis inotropy Antagonism of calcium paradox Hypotensive (central and peripheral action) Retardation of lesion development in calcium overload cardiomyopathy Increased resistance of platelets to aggregation

Action

References

system

Retina

185,253, 652,747 183,186,187,362, 643 183,187 Summarized in 315 145,402 1, 3, 68, 198-201, 322, 323, 539, 581, 699, 829 33,510

Maintenance of structure and function of photoreceptors, outer segments, and tapetum lucidum

248

Sperm motility

590, 741

Liver

Bile salt synthesis

243,244 Reproductive

factor

, 293

system 529,580

Muscle Brain

Anticonvulsant Modulator of neuronal excitability Maintenance of cerebellar function Antinociceptive against chemical stimuli Thermoregulation

Muscle membrane stabilizer 13,123-126,191,232,233,350, 538 55,'738-740

697 12, 59, 105, 106, 215, 276, 361, 460,532,634,698,700

Antiaggressive actions Central regulation of cardiorespiratory responses Alteration of sleeping duration Resistance to anoxia/hypoxia Altered learning Altered motor behavior Antitremor actions Suppression of drinking Suppression of eating

284,300

63,151,217,286,288,552

491,492 69,202,207,271,808

168,319,505,509 185,438,483,689 10,483, 662

General

Modulation of neurotransmitter and hormone release Osmoregulation Stimulation of glycolysis and glycogenesis Attenuation of hypercholesterolemia Cell proliferation and viability Antioxidation Regulation of phosphorylation Xenobiotic conjugation

419, 577a, 633,676,678,762,814 261,329,349,357,433 147,409,527,673 8, 29, 115, 279, 321, 382,

617 280,605 592,688,756,758,823 453,466 155,281,340-343,347,352

46,205,353,459,614,615

213 275,761

761

may be acting and how the same mechanism expressed in different settings may affect apparently unrelated physiological phenomena. I have, perhaps unwisely, listed conclusions at the end of each section. The need for brevity in language and the desire to avoid qualifying nearly every statement inevitably gives these conclusions an assurance that may be lacking in the primary literature. In attempting to make the information digestible to the general reader, I may have trodden on a few toes of the taurine specialists. However, there are enough toes in the area that a few can be spared in a good cause. If nothing else, I hope the conclusions stimulate further investigations by those desirous of disproving them. Despite the impressive progress of the past two decades, an understanding of the mechanisms underlying the effects of taurine has been slow to evolve. However, recent investigations have narrowed the gap between observation and understanding, and one can be confident that a further review of this topic in this journal in another 20 years will reveal an advance in mechanistic insight sufficient to systematize in a rational way the biological actions of taurine. It is a measure of the progress made over the last 22 vears that anv hoDe of competing with Jacobson and

Smith in publishing a complete and exhaustive review of the taurine area has vanished irretrievably, entombed within a voluminous literature. For those who want more information, the literature on taurine can be pursued through the numerous reviews and symposia proceedings that have appeared since 1976 (45,87,247,286, 288,291,297,298,305,311,327,338,416,549,551,598,672, 735, 823).

II.

PHYSICOCHEMICAL

CONSIDERATIONS

The biological actions of a compound are an inevitable consequence of its physicochemical properties. Taurine is an amino acid that differs from the more familiar substances of that class in being a sulfonic rather than a carboxylic amino acid and in being a P-amino acid rather than an a-amino acid. Compared with carboxylate groups, the sulfonate group is a strong acid, having an acidic dissociation constant (pK,) equivalent to that of a mineral acid, such as hydrochloric acid (Table 2). The high acidity makes taurine almost completely zwitterionic over the physiological pH range. In contrast, a significant fraction of carboxylic amino acids exist unionized over this range (Fig. 1). At pH 7.4, the fractions


PHYSIOLOGICAL

ACTIONS

January

1992

TABLE

2. Physical constants of neuroactive amino acids Solubility, 25°C

Taurine Glycine Aspartate Glutamate ,&Alanine GABA Asparagine Glutamine

838 3,329 37.6 58.4 Freely soluble Freely soluble 226 246

GABA, y-aminobutyric

mM

Ionization pK,

pK2

1.5

8,948 518 952

2.34 1.88 2.16 3.55 4.03 2.02 2.17

8.82 9.60 3.65 4.32 10.24 10.56 8.80 9.13

9.60 9.96

5.16 5.97 2.77 3.24 6.89 7.30 5.41 5.65

acid. [Modified from Huxtable (290).]

Taurine

7.0

7.2

7.4

7.6

7.8

PH

1. Effect of pH on degree of ionization of acid function in taurine, ,&alanine, and y-aminobutyric acid (GABA). Number of unionized functions per lo6 molecules is shown. FIG.

100

Isoelectric Point

pK3

of @-alanine and GABA having unionized acid functions are 125 and 340 times greater than the fraction of taurine. The zwitterionic nature of taurine gives it high water solubility and low lipophilicity. Consequently, compared with carboxylic amino acids, diffusion through lipophilic membranes is slow for taurine. Figure 2 illustrates this for the uptake of taurine and the structurally analogous ,&alanine by the isolated perfused heart. Both substances exhibit saturable active transport with similar kinetic properties. However, nonsaturable uptake for taurine (i.e., diffusion) is negli-

1===5=

103

Constants

100°C

4,170

OF TAURINE

Concentration

(mlvl)

FIG. 2. Transport of lipophilic amino acid, P-alanine, and lipophobic amino acid, taurine, into isolated Lagendorff-perfused rat heart. There is a nonsaturable component to transport of @-alanine, indicating membrane diffusion. [From Huxtable and Sebring (316).]

gible compared with the nonsaturable uptake of ,&alanine. The impermeability of biological membranes to taurine probably underlies the extraordinarily high concentration gradients that may be maintained across such membranes. For the retina, a taurine gradient of 400:1 is maintained (586). For brain cells, this may be as high as 500:l. For Ehrlich ascites cells in culture, the gradient ranges to 2,000:1 (102), and for HeLa cells it ranges up to 7,000:1(624). The poor permeability of taurine also permits ready renal regulation of the whole body content in mammals, as reuptake from the tubular fluid is a function of a hormonally controlled active transport system (95-97, 192, 345, 659). Hormone- and neurotransmitter-controlled regulation of active transport processes have also been established in the heart and salivary gland (283), the pineal gland (810,811), astrocytes (267), and glial cells (479). To maintain such concentration gradients by highcapacity, high-affinity uptake systems in the face of significant diffusion out of the cell would place an unacceptable energy demand on the cell. Sodium ions are cotransported with amino acids (297). Depending on the system and the observer, for each taurine molecule transported, between 1 and 3 Na+ are carried. This Na+ is pumped back out via the Na+-K+-ATPase, hydrolyzing 1 ATP per 3 molecules of Na+. The diffusion rate shown for P-alanine on Figure 2 is ~212 nmol min-l . mmol-l g dry wt? The taurine concentration in the rat heart is ~40 mM. If taurine diffused l

l


104

R. J. HUXTABLE

Volume

TABLE 3. Structural and ionic properties of taurine, ,&alanine, and aminoethane phosphonate

.

Average

Aminoethane phosphonate Taurine ,&Alanine

HNH

CNH

111.0

108.0 108.7 108.4

110.3

Around

Bond C,

Angles, Around

112.0 109.3 112.4*

O Cz

111.9 109.3 108.4-t

0x0

cxo

111.7 112.5 127.0

107.1 106.2 116.5

Bond Lengths, nm C-XX-O* Aminoethane phosphonate Taurine @Alanine

C-C

C-N

N-H$

0.180 0.153 0.151 0.148 0.178 0.146 0.152 0.148 0.155 0.129 0.155 0.148

0.095 0.085

Ionization

Aminoethane phosphonate Taurine @Alanine Aminomethane sulfonate

Cl--$

Cz-H*

0.102 0.096

0.102 0.096

Constants

PK

PK,

Isoelectric point

? 1.5 3.6 ?

? 9.08 10.36

5.29 6.99

out at the same rate as ,&alanine, to maintain a concentration of 40 mM taurine the heart would need to pump 17 pmol Na+ . min-l g dry wt? This is equivalent to 5.7 pmol ATP or almost 2 pmol 02. This may be compared with the O2 consumption of the working rat heart of 36.8 pm01 min-l g dry wt-’ (540). Furthermore, because the maximum rate (Vmax) of taurine transport in the rat heart is -32 nmol . min-’ .g dry wt-’ (308), the amount of the taurine transporter protein would have to be increased >250-fold to counteract such diffusion rates. As a result of its zwitterionic nature, taurine has a high dipole. Its isoelectric point falls between that of carboxylic w-amino acids, such as glycine, ,&alanine, and GABA, and that of acidic amino acids, such as aspartate and glutamate (Table 2). The membrane modulatory actions of taurine and its interactions with Ca2+ and other cations probably stem from its unique ionic characteristics. The overriding significance of the ionic properties of taurine is supported by the inability of isosteres of taurine to substitute for it in various biological phenomena. Aminoethane phosphonate and ,&alanine are two compounds that sterically resemble taurine (Table 3; Fig. 3). Despite the similarity, aminoethane phosphonate has no affinity for the taurine transport system or, indeed, for any other site at which taurine interacts. Aminoethane phosphonate differs from taurine in being a dibasic acid, i.e., it has two acidic replaceable protons, l

/

0

\ o

FIG. 3. Type structures for @aminooxyacids, taurine (X = S), P-alanine (X = C), and aminoethane phosphonate (X = P) (see Table 3).

and thus has a lower isoelectric point than taurine. P-Alanine does not mimic the Ca2’ modulatory action of taurine on phospholipid membranes and does not compete with taurine for its low-affinity phospholipid-binding site (692). The sulfur in taurine is in the form of a sulfonate and may be further oxidized to sulfate. The lowest oxidation state for sulfur is -2, and the highest is +6. The sulfur in taurine, at +4, has a free energy content of ~260 kJ/mol relative to sulfate (Fig. 4). However, animals are unable to garner metabolically this energy of oxidation, resigning to bacteria the responsibility of completing the natural redox cycle of sulfur (292).

5.75

For numbering see Fig. 7. Data for bond lengths and bond angles: aminoethane phosphonate (566), taurine (567), and ,&alanine (348). Ionization constants from Ref. (11). pK,, pK,, acidic and basic dissociation constants, respectively; X, variable element. *x-cl-&. t N-&-Cl. $ Averages.

l

HH I I N-C,-C,-X----O / I I H HH H\

72

III.

BIOCHEMICAL

CONSIDERATIONS

A. Distribution

of Taurine

The distribution of taurine can be summarized in the statement that it is present in high concentrations throughout the animal kingdom, except for the protozoans, but is low or absent in the other kingdoms. Although there is a body of literature on the transport and metabolism of taurine in bacteria (see sect. VIC), little information is available on the taurine concentrations in bacteria. It appears, however, that tau-

l

209 0

kJ SO 178 kJ k

l/2

s*o3 151 kJ so;-

,

+4 258

kJ

+6 FIG. 4. Free energy of oxidation of sulfur. Each step down removes 2 electrons with indicated drop in free energy. Sulfur in taurine is at oxidation state of +4. [From Huxtable (294).]


January

1992

PHYSIOLOGICAL

ACTIONS

rine is found in certain bacteria in relatively low amounts. In Bacillus, for example, taurine concentrations increase during cell growth, reaching a maximum of 0.6 pmol/g protein (536). However, taurine is obtained from the incubating medium and not biosynthesized. In the plant kingdom, taurine occurs in traces, averaging -0.01 pmol/g fresh wt of green tissue according to one report (424). This is ~1% of the content of the most abundant free amino acids. Marine algae (seaweeds) are an exception. In Japan, processes have been patented for the extraction of taurine from seaweed (748). Yields were not reported. However, seaweeds in general have relatively high concentrations of taurine, concentrations falling in the range of 0.015-0.998 pmol/ g wet wt, depending on the species (358). Taurine and its derivative N-(1-carboxyethyl)taurine are reported to have a widespread distribution in red but not in brown or green algae (420). Again, however, no concentrations are given. Mushrooms, lichens, mosses, and ferns contain no more than 0.001-0.007 pmol/g wet wt (358). Taurine has been found in pumpkin seeds at concentrations of 0.013 pmol/g wet wt and in nuts such as walnuts and almonds in concentrations ranging up to 0.046 pmol/g wet wt (600). Others were unable to detect taurine in a range of food grains and nuts, including rice, corn, wheat, barley, lentils, and peanuts (597). Concentrations of ~0.005 pmol/g dry wt were found in black beans. Methodological difficulties obtrude in the measurement of such low concentrations of taurine. In some of the reports, it is unclear as to whether or not glycerophosphoethanolamines interfered with the assay (130, 745). In brain tissues, the coelution of such substances can give erroneously high values for taurine and in plant extracts can lead to a false identification (383). Typically, taurine concentrations in the brain as measured chromatographically will fall following acid hydrolysis of a sample (130,745), as such a treatment cleaves glycerophosphoethanolamine to ethanolamine and glycerophosphate. We have found no taurine in beans (Mexican black, white, or tan) or peanuts (R. J. Huxtable and C. Bergland, unpublished observations). In extracts of beans, a major peak elutes close to, but clearly different from, the retention time for taurine. However, in the absence of appropriately run standards, the peak could be misidentified as taurine. “Spiking” samples with aglycerophosphoethanolamine showed that the unknown peak did not coelute. Its identity remains unestablished. A further problem lies in the potential for plant contamination by mammalian effluvia. One wet thumb print contains 1 nmol of taurine (236). This amount may be compared, for example, with the analytical range of 0.1-0.3 nmol employed by the high-performance liquid chromatographic method used in one recent paper reporting concentrations in plants (600). Grains, seeds, and other plant products may be contaminated with taurine by rat droppings, insect remains, or poor handling by laboratory personnel. Reported values may therefore be taken as representing upper limits of taurine content. Among the invertebrates. marine arthropods and

OF

105

TAURINE

molluscs are, in general, high in taurine (15,16,160,430, 607,616,772,794). Concentrations have been reported to range from 12 pmol/g wet wt in an unidentified species of shrimp to 41 pmol/g wet wt in a clam (600). The peripheral nerve of the crab, Carcinus maenas L., has 75.5 pmol/g wet wt of taurine, and the ganglions are equally high (160). However, concentrations of certain other amino acids are also high. Aspartate concentrations are higher than taurine in the peripheral nerves of both crabs and lobsters. Taurine concentrations in marine invertebrates were thoroughly reviewed in 1971 (15). The insects comprise another class high in taurine. It is the most abundant free amino acid in the nervous system (671). Honeybee brains contain 34.4 pmol/g wet wt (193), and brains of stable flies, Stomoxys calcitrans, contain 37.3 pmol/g dry wt (266). Fly ganglions are even higher at 110 pmol/g dry wt. Spiders are unusual in having higher concentrations of taurine than of glutamate in their CNS. Taurine can comprise up to 34% of the total free amino acid pool, being particularly high in spiders using vision for orientation (521). In fish, taurine is common. Indeed, some of the concentrations reported are remarkably high: 83 pmol/g wet wt in the dark muscle of the yellowtail, Seriola quinqueradiata, for example (660). Tilapia contains a more modest 9.1 pmol/g. The heart of the rainbow trout, SaZmo gairdnerii (Richardson), contains 48.7 pmol/g, and the gills contain 35.2 pmol/g of taurine compared with 0.73 pmol/g in plasma (219). Although not directly stated, these values are probably based on wet weight. The second most abundant free amino acid in the heart is glutamate, with only 2.2 pmol/g. Although taurine concentrations are generally low in reptiles, olive sea snakes, Aipysurus Zaevis, have plasma concentrations of 130 PM, and garter snakes (Thamnophis) excrete high concentrations of taurine (53). Frog brains have only 0.05 pmol/g wet wt (193). Birds, like fish, contain exceptionally high taurine concentrations in erythrocytes, typically 100 times the concentrations found in mammals (708). Pigeon erythrocytes, for example, contain 17 mM taurine. Concentrations are maintained by transport rather than by biosynthesis. In mammals, taurine is near ubiquitous in distribution, with tissue concentrations typically in the micromole per gram wet weight range. Body fluids, such as plasma, cerebrospinal fluid, and extracellular fluid, contain much lower concentrations, typically in the range of lo-100 PM. The highest concentrations are usually found in the heart or brain, but the bulk of the taurine is in the musculature. In the heart, taurine comprises up to 60% of the total free amino acid pool. Concentrations range from 3.5 pmol/g wet wt in cows to in excess of 30 pmol/g in rats (284). Numerous reports are available on taurine concentrations in the brain and spinal cord (6,7,47,48,112,120, 228,254,355,426,551,555,557,558,568-570,610-613,625, 705,781,836). In adult brain, taurine concentrations

tvgicallv

slightlv

higher

or slightlv

are lower than GABA


106

R. J. HUXTABLE

concentrations. Glutamate concentrations, however, are consistently higher. Microdistribution of taurine within a given structure tends to be uniform (836). In rats, taurine is high in the cerebral cortex and cerebellum. The olfactory bulb is another region rich in taurine. All cell types in the CNS appear to contain taurine. Kainic acid destroys neuronal cell bodies while sparing glialcells (114,237,435,445,601,731,751). Injected unilaterally into rat striata, kainate produces a 14% decrease in whole tissue taurine content relative to the unlesioned side and a 29% fall in taurine content of the brain P, fraction (a synaptosomal and mitochondrial fraction) (629, 828). Measurements of tissue taurine concentrations following selective destruction of cerebellar granule or stellate cells also indicate the presence of taurine in a number of cell types (642). In rabbit cerebral cortex, taurine, along with other neuroactive amino acids, was reported to be present in higher concentrations in glia and synaptosomes than in neuronal cell bodies, the perikarya (696). Glial tumors also contain taurine (434). The highest concentrations of taurine occur in developing brain, at which time the concentrations of other free amino acids tend to be low (131). With development, taurine concentrations fall, with levels in adults being about one-third those of neonates. This pattern has been observed in humans (434, 737), monkeys (641, 737), mice (384), rabbits (91), and rats (127, 287,310,732,733). This developmental pattern is true in insects also. Taurine concentrations in the brain of the moth, Mamestra cmfigurata, rise ZO-fold between the pupal stage and metamorphosis (61). Pinched-off nerve terminals, or synaptosomes, have been well-studied preparations (64,131,383). Synaptosomal taurine concentration is about the same as whole tissue concentration. Synaptosomal concentrations of nearly all other amino acids are lower than whole tissue concentrations, leading to a relative synaptosomal enrichment in taurine. Synaptic vesicles contained within synaptosomes are even more enriched in taurine. Thus, in bovine cerebral cortex, taurine concentration is 25.6 pmol/g protein, this being 9.9% of the ninhydrin-positive material in the preparation. Corresponding figures for synaptosomes are 11.0 pmol/g protein (12.9%) and for synaptic vesicles 55.9 pmol/g protein (37.4% ) (383). In bovine medulla, taurine comprises 10.3% of ninhydrin-positive material in whole tissue and 33.8% in synaptosomes. However, synaptic vesicles contain x0.04 pmol taurine/g whole brain, which is only a few percent of the total taurine content of the brain. In all species examined, the concentrations of taurine in retina exceed those of the brain (585,591). Retinal concentrations are high even in species low in taurine in other tissues. In mammals, concentrations are fairly constant from species to species, with baboons having 29 pmol/g wet wt retina, guinea pigs 32 pmol/g wet wt retina, cats 43 pmol/g wet wt retina, rats 50 pmol/g wet wt retina, and rabbits 52 pmol/g wet wt retina (585, 591, 792). Mice are exceptional in having only 16 bmol taurine/g wet wt retina. Reptiles and am-

Volume

72

phibians typically have concentrations one-third to onefourth those of mammals, the frog having 10 pmol/g wet wt retina. The layered organization of the retina makes it possible to dissect and analyze separately the various cells of which it is comprised (108,109,579,832). About twothirds of the retinal taurine is localized in the photoreceptor layer. The concentration is highest in the outer nuclear layer, 95% of the volume of which is photoreceptors, the other 5% being glia (595). Localization in the photoreceptor layer is confirmed by measurements on animals lacking photoreceptors, either due to inherited dystrophies or to experimental manipulations. In the so-called RCS rat (from their discovery at the Royal College of Surgeons, London), the photoreceptor layer degenerates over the first several weeks of life. Concomitantly, retinal taurine concentrations fall to 25% of those in normal rats (679, 681). Similarly, taurine concentrations are low in the retinas of mice with receptor dystrophy (109, 578, 579). Taurine concentrations fall in parallel with photoreceptor cell degeneration in Irish setter dogs with rod-cone dysplasias (680). Treatment with the excitatory neurotoxins, glutamate and kainate, destroys the inner layer of the retina without affecting the photoreceptor layer. Such treatment leaves taurine concentrations unaffected (601, 661). The developmental changes in taurine in the retina differ considerably from those in the brain in that taurine concentrations increase in temporal correspondence with the formation of the photoreceptor layer and the development of electroretinogram amplitude (583). Secretory structures, such as the pineal, pituitary, and neurohypophysis, contain extremely high concentrations, ranging to in excess of 60 pmol/g wet wt (120, 220,225,228,369,464,785).

In a given species, taurine concentrations are most variable in the liver where the concentrations are affected by the dietary content. Rabbits and guinea pigs have low hepatic concentrations of taurine (91, 821). Newborn rabbits have concentrations of taurine in liver 100 times greater than adult rabbits (91). In summary, perhaps the most striking observation concerning the distribution of taurine is its generally high concentration in cells lacking cell walls and its almost complete absence from cells having cell walls. In mammals, taurine is particularly high in excitable tissues, especially in secretory structures. I. Conclusions on distribution of taurine

I) In the plant kingdom, the distribution of taurine is sporadic and where found the concentrations are low (nmol/g wet wt). Z) In the animal kingdom, except for the protozoans, the distribution of taurine is ubiquitous and the concentrations are high (pmol/g wet wt). 3) In general, taurine concentrations are high in species having cells lacking rigid cell walls and are low or absent in species having cells with rigid cell walls.


January

PHYSIOLOGICAL

1992

ACTIONS

4) In animals, taurine concentrations are high in platelets, electrically excitable tissues, and secretory structures (up to ~60 pmol/g wet wt). Concentrations are low in extracellular fluids (low PM) and are low or variable in other tissues. B. Metabolism

of Taurine

Taurine was for a long time generally considered to be the inert waste product of sulfur metabolism in animals. Although a long list of actions of taurine has now been established (Table I), in a sense one of the adjectives is correct and the other partially so. Taurine is chemically inert. It is biochemically inert in animals in the sense that the greatest proportion of taurine is excreted unchanged. It is, in animals, one of the end products of sulfur metabolism. The phrase end products is used advisedly, despite its superfluistic construction, as the word waste perhaps carries pejorative connotations one might wish to avoid. Detailed discussions of taurine biosynthesis can be found in recent reviews (293,297). Mammals are capable only of sulfur oxidation, not reduction. Reduced sulfur, in the form of the sulfur-containing amino acids methionine and cysteine, is therefore an essential component of the diet. Sulfur catabolism occurs by two routes, forking from the oxidized metabolite of cysteine, cysteine sulfinic acid (Fig. 5). Cysteine sulfinate is produced in the liver by cysteine dioxygenase (EC 1.13.11.20) (4’71, 725). It is rapidly metabolized further in all mammals by transamination to P-sulfinyl pyruvate and in some mammals by decarboxylation to hypotaurine. ,&Sulfinyl pyruvate spontaneously decomposes while still bound by its parent enzyme to sulfur dioxide and pyruvate.

107

OF TAURINE

Sulfur dioxide is rapidly metaboli zed to first sulfite and then sulfate, which is excreted in the urine. The hypotaurine originating from the other tine of the fork is oxidized further to taurine. In mammals, taurine is either excreted as such or in the form of bile salts such as taurocholate. The free energy associated with the oxidation of sulfur is wasted in animals, as they are unable to couple it to ATP synthesis. Sulfur passing through the transaminase pathway is merely excreted. The pathway through taurine, however, salvages the sulfur for other uses before it is excreted. Animals such as cats, humans, and certain monkeys that are unable to synthesize meaningful quantities of taurine must rely on a dietary source of this supposedly “waste” sulfonic amino acid. The mammalian handling of taurine is a small part of the biological sulfur cycle. In the biosphere, sulfate is reduced to sulfide by microorganisms and reoxidized to either sulfate or taurine by animals, microorganisms, and plants. The taurine excreted from animals is oxidized by certain microorganisms to sulfate to complete the cycle (292). In species other than mammals, taurine biosynthesis has been poorly studied. If the skate, Raja erinacea, is an exemplar, fish lack cysteine sulfinic acid decarboxylase and are unable to synthesis taurine (367). Embryonic skates are unable to convert [14C]cystine to taurine, relying instead on a transport system for extracting taurine from the egg yolk (216). The skate is also unable to metabolize taurine; it obtains it from the environment and releases it back into the environment (366). In conclusion, most reduced sulfur, ingested in the form of methionine and cysteine, is oxidized in mammals through cysteine sulfinate to sulfate. A small per-

CHgSCH2CH2FH+JH2 C02H Methionine

L

1

Cysteine Sulfinate 1 Decarboxylase

H02SCH2TH-NH2 k02H

H02SCH2CH2NH2 1

1

Hypotaurlne

Cysteine Sulfinate

I

SO2

Aspartate Aminotransferase

H2S03

-----b

Bile

Salts

44

1

H03SCH2CH2NH2

Taurine

Sulfite

+6

Oxidase

+ I

---b

Excretion

FIG. 5. Hepatic catabolism of sulfur amino acids in mammals. Bulk of sulfu .r amino acids is oxidized to cystei ne sulfinate. Further oxidation to sulfate is ubiquitous. Certain mammals also divert part of flow through cysteine sulfinate toward syn.thesis of taurine. Taurine is excreted as such or in form of bile salts such as taurocholate.


108

R. J. HUXTABLE

centage is metabolized to taurine. Certain carnivorous or omnivorous mammals, with their greater specialization, have lost, or are losing, the ability to produce taurine, relying instead on nutritional sources to maintain their body loads. Despite this, quantitatively, the vast bulk of taurine in the biosphere is formed in the animal kingdom. In most species, cell, organ, and whole body taurine concentrations are regulated by transport, biosynthesis and metabolism being of minor import. I. Conclusions

on metabolism

of taurine

I) Mammals metabolize sulfur amino acids through cysteine to cysteine sulfinate to sulfate. Mammals also metabolize cysteine sulfinate to taurine. However, the capacity to do this is highly variable by species. 2) Mammals unable to decarboxylate sufficient cysteine sulfinate must rely on a dietary source of taurine. 3) Taurine is excreted as such or in the form of taurocholate or related bile salts. Some mammals have lost the ability to conjugate taurine to form bile salts (see sect. VIE and Table 5). IV.

NONMETABOLIC

ACTIONS

OF TAURINE

The nonmetabolic actions of taurine are those that are not a result of a process in which taurine is either produced or metabolized. A. Osmoregulation

The phylogenetically oldest function for taurine and, next to bile salt synthesis, the one on a surest experimental footing, is that of osmoregulation. This is clearly an important function in numerous, but not all, invertebrates and fish. There is increasing evidence that it may be a similarly important function of taurine in mammals. Simultaneous with the evolution of cells arose the requirement for osmoregulation. Membrane excitability derives from ionic imbalances across the membrane. If the consequential osmotic imbalance were left uncorrected, alterations in cell volume would result due to the free permeability of plasma membranes to water. Increased cell volume leads to membrane rupture, while both increases and decreases in cell volume cause concentration changes in a plenitude of cell constituents and disruption of the biochemical processes sustaining viability. Cells can use one of three strategies for handling osmotic stresses. Osmotic changes can be ignored (by means of a cell wall), avoided (as in the shell-closing behaviors of certain molluscs), or adapted to (by modification of cellular concentrations of water, inorganic ions, and organic osmolytes). Organisms with cell walls, such as plants and most bacteria, can ignore osmotic changes within a certain range because the rigidity of

Volume

72

the wall prevents SWpelling. The cellulose walls plant cells permit internal turgors as high as 50 atm in some species. Organisms without cell walls face the dual problems of protecting body fluids from osmotic changes in the environment and osmoregulating cells in the face of concentration differentials across the plasma membrane. Multicellular organisms, such as molluscs, that can avoid changes in exterior osmolarity (i.e., mosmol/l solution) by such behaviors as shell closing still have need for intracellular osmotic regulation. Isosmotic intracellular regulation is indispensable for viability for single-celled organisms lacking cell walls or for multicellular organisms in which the osmolarity of body fluids approximates that of the environment. In general, marine invertebrates have body fluids isosmotic with sea water. In extracellular fluids, osmotic balance is achieved primarily with inorganic salts, while intracellular regulation is achieved with a mixture of salts and organic substances. The later evolution of anisosmotic extracellular regulation of body fluids (i.e., the osmolarity of extracellular fluids being held constant in the face of varying environmental osmolarity) partially relieves responsibility from the intracellular mechanism in vertebrates. The osmotic pressure of a cell is determined by the total osmolarity of cytoplasmic solutes. These solutes consist of inorganic ions, low-molecular-weight organic compounds, and macromolecules. Osmoregulation involves alterations in the concentrations of substances in the first two classes. Typically, in response to a hypo- or hyperosmotic stress, changes in concentration occur in selected members of both classes. In particular, K+ or Cl- accumulation or release is usually involved in osmoregulation (80, 654). However, with inorganic ions the requirements for osmoregulation and the regulation of membrane excitability are not coincident, constraining the osmoregulatory role of inorganic ions. In marine invertebrates and cartilaginous elasmobranch fishes (i.e., sharks and rays), organic substances contribute ~60~70% of the total cell osmolarity. The composition of the organic substances employed can vary widely. Intracellular urea varies from 2 mM in the hagfish, Myxine glutinosa, to 422 mM in the coelocanth, Latemeria chalumae, while free amino acids vary from 44 mM in the freshwater teleost, Platichthysjlesus, to 331 mM in the hagfish (368). Depending on the species, other important osmoregulators include trimethylamine oxide, sarcosine, and ,&alanine. In mammals, the largest contribution to the osmolarity of a cell is provided by inorganic ions. Osmotic regulation is provided by organic osmolytes, which typically contribute lo20% to the total intracellular osmolarity. What are the characteristics of an ideal osmoregulatory organic substance? The cytosolic concentration must change in concert with the osmolarity of the cell exterior. Changes in concentration must not drastically alter cell membrane potential, enzyme activities, or other cell processes. To satisfy these requirements, the osmotic change must be close to electrogenically neutral. To avoid interference with an osmoregulatory


January

1992

PHYSIOLOGICAL

ACTIONS

function by competing metabolic demands, ideally one would want a metabolically inert or nonessential compound. Furthermore, the energy expenses of synthesizing the compound, maintaining high concentration gradients across the cell membrane, and changing concentrations in response to osmotic changes must all be minimized. Thus a zwitterionic compound(s) is indicated, for a neutral compound would be liposoluble and require energy for maintenance of high cell concentration gradients. The requirement of inexpensive synthesis can be met by using a metabolic waste product such as taurine or urea. For adjusting the concentration gradient across the membrane, a selective transport system is needed, one that is sensitive to osmotic changes. Cells can be categorized according to the low-molecular-weight organic compounds they use for osmoregulation. Some species, such as certain molluscs, use primarily taurine. Other species use taurine to adapt to limited osmotic changes but, in addition, adjust the concentrations of other cell osmolytes in response to severe osmotic stress. Still other species, such as the blue crab, Callinectes sapidus (Zll), use a mixture of osmolytes, including taurine. Finally, certain cells do not use taurine at all to respond to osmotic stresses. Examples include bacteria, where other nonessential amino acids such as glutamate, proline, and GABA serve as osmoregulatory substances (513), and the mollusc, Anodonta, where phosphate and K+ are the major osmotic substances. Among the amino acids, the largest variation under osmotic stress is always provided by the nonessential amino acids (210,682, 683). Taurine meets the requirements for a biologically perfect osmoregulator almost ideally. It is transported by a system unique to ,&amino acids, the transport is Na+ dependent (i.e., responsive to ionic changes), and the transport is responsive to other osmotic substances, such as glucose (31,779). Extremely high intra- to extracellular concentration gradients for taurine can be maintained due to its lipophobic properties, and the use of taurine as an osmoregulator “spares” metabolically important amino acids. It is hardly surprising, therefore, that an osmoregulatory action of taurine was the first biochemical function to evolve for it and that this action has been conserved so strongly from amoebas through the mammals. The involvement of taurine in maintaining osmotic balance was suggested in 1915 to account for the high taurine content of the echinoderm Astropecten aurantiacus (Grey) (401). An osmoregulatory function for taurine appears to have been first proposed by Krogh (404). Typically, taurine concentrations are high in marine molluscs (421, 715), low in molluscs living in brackish water, and absent in land and freshwater molluscs (32, 715). Volume regulation by taurine has subsequently been established in systems as diverse as euryhaline species (178), avian erythrocytes (403, 708, 719), and mammalian cells (252, 655, 658). Euryhaline species are aquatic organisms that are able to adapt to marked changes in salinity: they can move from saltwater to brackish or freshwater and vice

109

OF TAURINE

250

175

200

50 r 150 E L 2 7

100

50

Sea water

salinity,

FIG. 6. Relationship between salinity and total body concentration of taurine (crosses) and total ninhydrin-positive substances (NPS; closed circles) in mussel MytiZus edulis. Note that with increasing salinity, taurine constitutes increasing percentage of total ninhydrin-positive substances. [From Lange (430). Reprinted with permission by Pergamon Press.]

versa. Such moves are marked by osmoregulatory shifts in cell constituents. In many cases, taurine is the constituent showing the largest shift (30,111,196,197,329,349, 359,433,790). In clams such as Noetia ponderosa, taurine is the major osmotic amino acid, its concentration varying from 68 pmol/g dry wt in adductor muscle to 356 pmol/g dry wt in gills. In the latter structure, taurine plus hypotaurine comprise 80% of the free amino acid pool. When N. ponderosa blood cells are moved from seawater to 50% seawater, the fall in cell taurine concentrations provides 86% of the osmotic change (21). Taurine is also prominently involved in osmoregulation in the mussel, Mytilus e&,&s (632, 665). As salinity increases, the percent contribution of taurine to the ninhydrin-positive pool also increases. At a salinity of 5 parts per thousand (ppt), taurine is undetectable. At a salinity of 30 ppt, taurine constitutes 28% of the ninhydrin-positive pool (Fig. 6) (430). In the shellfish Crassostrea, as salinity increases, the cell concentrations of both taurine and glycine increase (478). Taurine provides >50% of the osmotic increase in mudflat snails, Nassarius obsoletus (Say), exposed to increased salinity (357). In euryhaline teleosts (an infraclass of bony rayfinned fishes), the osmolarity of body fluids changes with environment. Serum osmolality (i.e., mosmol/kg solution) in the flounder, for example, drops from 364 to 304 mosmol/kg on transfer from seawater to freshwater. In the stickleback, Gasterosteus aculeatus, the corresponding drop is from 340 to 290 mosmol/kg (431). Isosmotic intracellular regulation therefore occurs as the


110

R. J. HUXTABLE

environment changes. Typically, this is largely achieved by changes in taurine content. Taurine is particularly important in osmoregulation of the fish heart (181,790, 791). Taurine comprises in excess of 50% of cardiac free amino acids in teleost species such as flounder (Hatichthysjlesus) or skate, and changes in taurine content accounts for about one-half of the osmolar adjustment in the cell (790). When the osmolality of flounder plasma decreases by 17%, the fall in ventricular taurine provides 40% of the total osmotic adaptation, with K+ providing 16% (791). As plasma osmolality shifts, so does the concentration ratio for taurine between plasma and erythrocytes (197). A 100 mosmol/kg fall in the plasma is accompanied by an 80% drop in erythrocyte taurine concentration, providing 30% of the total osmotic response. The fall in GABA is even more marked. However, GABA provides only 17% of the total osmotic response (194). Taurine excretion from the little skate, Raja erinacea, is increased under hyposmolar conditions (366). On transfer from sea water to 50% sea water, the muscle of the little skate shows marked drops in free amino acid, urea, and trimethylamine oxide concentrations (180). An area of progress in the taurine field ov ‘er the past decade sterns from the realization that cell osmoregulation is probably a significant function of taurine in mammals also. In mammalian heart (760) and brain (759), taurine can be the organic osmolyte present in highest concentration. The largest shift in osmolar equivalents within a cell in response to osmotic stress is contributed by taurine. This is as true of mammalian cells responding to a change in cell environment as of marine organisms responding to a change in salinity (181,212,259, 768). Thus dilution of the incubation medium results in a release of taurine by a Na+-independent mechanism (261). A 30% increase in cell volume in Ehrlich ascites cells produces a 600% increase in permeability to taurine but only a 50% increase in permeability to g,lycine An osmotic change from 300 to 150 mosmol/kg leads to an 87% fal 1 in cell taurine co ncentration and a 1,500% rise in buffer taurine concentration. In other words, the concentration gradient across the cell membrane for taurine drops from 757:1 to 7:l. The permeability of the membrane to taurine is a linear function of cell volume (261; Fig. 7). Ehrlich ascites tumor cells behave as almost perfect osmometers. Taurine is the most significant ninhydrin-positive substance lost during volume regulation, but even bigger changes occur with K+ and Cl- (260). On shifting the cells from a 300 mosmol/kg solution to one of 225 mosmol/kg, there is a loss of 21.8 mM ninhydrinpositive substances from the intracellular milieu but a loss of 47.2 mM inorganic ions (Na+, K+, and Cl- combined). However, the steady-state distribution of amino acids across the cell membrane varied with the concentration gradient of K+ and Na+ across the membrane (260). Ion transport is powered by a Na+-K+-ATPase, and amino acid transport is Na+ dependent. Thus energy consumption, ion gradients (hence cell excitability),

Volume

72

50 A

4o

z $ y* 30

z g + 2. [ (L 10

P

oh-

1

1.1

1.2

1.3 Relative

cell volume

FIG. 7. Cell volume and amino acid permeability. As relative volume of murine Ehrlich ascites cells is increased, there is marked and linear increase in taurine permeability (A). Change in glycine permeability (B) is much less marked and nonlinear. Incubation media contain 10 PM taurine (X), 1 mM glycine (o), or 0 glycine (0). [From Hoffmann and Lambert (261).]

and amino acid accumulation are all linked phenomena. Taurine concentrations are typically high in mammalian sperm and seminal fluid, and it is possible that taurine is serving an osmoprotective function. In hamsters, fluids in the reproductive tract are hyperosmolar, having values of up to 400 mosmol/kg (344). Hyposmotic conditions kill sperm, but chimpanzee sperm are protected by the addition of 2 mM taurine (580). The high-affinity transport system for taurine in mice myocytes responds sensitively to changes in osmolarity (31). Rats with hereditary diabetes insipidus are chronically dehydrated. Water deprivation leads to increased taurine concentrations (per g protein) in muscle, brain, and platelets, suggesting an osmoregulatory function for the compound (541). The loss of taurine from isolated retinas varied inversely with osmolarity; the greater the osmolarity the lower the efflux (687). The excitotoxin-induced release of taurine from retina is stimulated by both K+ and Cl(593). As the edema produced by excitotoxins is thought to be a consequence of passive influx of Cl- accompanying increased Na+ conductance, Cl-enhanced taurine efflux may be a link between cell volume changes and the initiation of an osmoregulatory response. Taurine has often been shown to protect various functions of retinal rod outer segments. Rod cells are one of two types of photoreceptors in the retina, the other type being cone cells. The outer segments of rod cells can be readily isolated. Each outer segment consists of from l,OOO-2,000 disks, stacked like dinner


January

1992

PHYSIOLOGICAL

ACTIONS

plates, surrounded by a membrane (66). The rod outer segment is biochemically hyperactive. New disks are continuously biosynthesized at one end of the rod and are continually shed from the other end in groups of 8-30 (838, 839). The protective effect of taurine is complex and appears to involve not only osmoregulatory but antioxidant and ion regulatory activities. Light exposure causes an increase in diameter in rod outer segments (158), probably secondary to alterations in ionic fluxes. Taurine, which is found in these structures in high concentration, may be a regulator of these volume changes. Under certain conditions, ferrous sulfate causes peroxidation, swelling, and disruption of rod outer segments (590). Swelling can occur secondarily to lipid peroxidation (90, 819). Taurine and zinc sulfate together protect against the swelling without affecting malondialdehyde formation, an index of degree of peroxidation. @-Alanine also protected against the swelling, suggesting an osmoregulatory action of these P-amino acids. The brain is particularly vulnerable to osmotic disturbances (517, 572, 713). Cerebral edema is a serious condition, leading to seizures and other sequelae, that is hard to treat (22,26,27,133,743). Taurine has anticonvulsant actions in a wide variety of experimental seizure states (286). These actions may stem, in part, from its osmoregulatory action, although an endogenous anticonvulsant action has yet to be demonstrated for taurine. The mammalian brain alters cell amino acid concentrations in response to both hypo- and hyperosmotic conditions, decreasing them in the former and increasing them in the latter condition (50). During the regulatory phase, astrocytes under hyposmolar conditions show a marked and unique increase in taurine efflux, which depletes cell taurine content by up to 64% (623a). Astrocytes swell when incubated in as little as 10 PM taurine, perhaps because too much enters the cell (797). The toxicity of taurine is usually assumed to be negligible, but such findings suggest that exposure to high amounts of taurine may carry cryptic risks. The swelling of astrocytes leads to a proportional depolarization of membrane potential (365). This is an indication that the osmoregulatory and electrical activities of cells are interdependent phenomena. The frequently studied effects of taurine on ion currents may thus be closely connected with its osmotic actions (297). Taurine is also toxic to cultured cerebellar cells from kittens, lowering survival rate (770). In mice cells, however, taurine supports cell survival. Water intoxication both increases extracellular taurine concentrations and decreases intracellular levels (720, 795). A decrease in extracellular osmolality of as little as 10 mosmol/kg leads to detectable increases in taurine concentrations. A 15-fold increase is seen at a 105-mosmol/kg decrement. Microdialysis of the brain with hyposmotic solutions resulted in marked increases in extracellular taurine concentrations (720,795). No other amino acid was

OF

TAURINE

111

affected at decreased osmolalities of up to 50 mosmol/ kg. If osmolality is decreased further, then an increased release of other amino acids is found (437). Perfusion with a 105 mosmol/kg buffer led to a rapid 15-fold increase in taurine concentrations. On switching to a standard Krebs Ringer bicarbonate buffer, taurine concentrations promptly reverted to normal. Systemic water intoxication (ZOO ml/kg ip) also led to increased extracellular taurine concentrations in the brain within 60 min. Results such as these suggest that the osmoregulatory actions of taurine in mammals have both an intracellular and an extracellular component; in the face of an osmotic imbalance, the taurine concentration in the intracellular compartment alters inversely to the taurine concentration in the extracellular compartment. In the continuing biological demonstration that everything is connected to everything else, disturbances in osmoregulation are involved in the response of brain cells to excitotoxins and the response of photoreceptors to light. Excitotoxins are neuroexcitatory acidic amino acids such as kainate, glutamate, N-methyl-D-aspartate, or cysteate. They kill neurons. The cell depolarization these agents produce is accomplished by increased Na+ entry. There is a resulting passive Cl- entry. Water enters to counteract the osmotic action of Cl-, the cells swell, and lysis may result (657). In general, conditions that lead to swelling of brain cells result in a stimulated efflux of taurine. These conditions include seizures (796), excitotoxins (78,445,788), ischemia (51), and hypoglycemia (763). The taurine-depleting agent, guanidinoethane sulfonate, can replace taurine as an osmoeffector in the brain (768). In summary, osmoregulation is not a function unique to taurine. In fish and in marine invertebrates, taurine serves a prime osmoregulatory function, i.e., the variations in taurine content of a tissue are sufficient to account for a significant proportion of the osmotic adjustment of that tissue. In mammals, the osmotically induced variations in taurine content in general account for only a few percent of the osmotic change required. Taurine, to fulfill an osmoregulatory function, must do so by modification of the movement of other osmotically active substances, such as ions or water. It has been pointed out that in the brain there is a linear correlation from mammal to mammal in the taurine content and the cerebral metabolic rate or rate of glucose consumption (780). As glucose entry and metabolism are accompanied by the entry of water, it has been suggested that taurine is involved in the removal of this water. On the other hand, the correlation between glucose consumption and taurine is heavily weighted by two small species, rats and mice, with high metabolic rates. Other small species should be considered to strengthen the correlation. In general, phenomena such as seizures or hypoxia that interfere with cell water balance in the brain also alter taurine balance.


112 1. Taurine

R. J. HUXTABLE

uptake

The transport and release of taurine are processes integrally involved in any osmoregulatory function. These phenomena have been reviewed in detail recently (297). The increase in cell taurine content produced by hyperosmolar conditions appears to be achieved primarily by active transport of taurine into the cell (31). This is a Na+-dependent process, with Na+ being cotransported into the cell. The coupling to Na+ supplies the energy for transport, inasmuch as the concentration gradient the Na+ is running down is maintained by a membranebound Na+-K+-ATPase. An increase in the extracellular Na+ concentration may also serve as a signal that the osmotic strength is rising. In addition, taurine uptake is stimulated by extracellular Cl- (345, 820, 841). In fish renal tubules, replacement of Cl- led to a fall in the Vmax for taurine transport (820). The incomplete resorption of taurine by renal proximal tubules and the dependence of resorption on various hormonal and second messenger signals allow the kidneys to regulate the whole body taurine burden in mammals (129,345). Thus, in rats, the rate of exchange of taurine between body organs is faster than the turnover rate from the whole anima 1, indicating that excretion is the rate-limiting step rather than release into the circulation (287). For example, rats fed a diet containing 0.4% taurine had half-lives of exchange of 4.9 days for visceral organs, 5.5 d.ays for the brain, and 11.4 days for whole body turnover 2. Taurine

release

The drastic drop in erythrocyte taurine content produced by hyposmolar conditions is a consequence of a marked stimulation in taurine efflux. The permeability of the plasma membrane to taurine rises, and, due to the steep concentration gradient across the membrane, taurine efflux increases. That this is the mechanism is shown by the finding that both the influx and efflux rate are stimulated (although, because of the concentration difference across the membrane, the mass transfer is out of and not into the cell) and that the influx is not Na+ dependent (195). This indicates both the lack of identity of this erythrocyte system with the normal Na+-active transport process that maintains cell taurine concentrations and its lack of energy dependency, i.e., taurine is entering the erythrocyte by diffusion rather than by carrier transport. The signal for the permeability change could be water movement, osmotic change per se, or stretch of the plasma membrane. In the rectal gland of the shark, Squalus acanthias, the permeability to taurine is increased by K+ (841). A 30% decrease in medium osmolarity leads to a l&fold increase in taurine efflux from chick retina (603). The efflux rate of taurine from flounder erythrocytes increases some 40-fold within a few minutes of buffer osmolality being dropped by 75 mosmol/kg (195; Fig. 8).

Volume

72

100

“0 -80

0 I 0

I

I 80

I 160 Time

I

I 240

1 320

(min)

FIG. 8. Taurine efflux and cell osmolality. Flounder erythrocytes were transferred from medium of 330 mosmol/kgH,O (open circles) to medium of 225 mosmol/kgH,O (closed circles). Na+ was held unchanged at 113 mM and taurine at 0.3 mM. Lowered osmolality produces immediate and marked stimulation in rate coefficient for taurine efflux. [From Fugelli and Thoroed (195).]

As is typical of cells exposed to hyposmolar conditions, the erythrocytes initially swell and then revert to the initial cellular volume as volume-adjustment mechanisms come into play. In this system at least, stimulation of taurine release is stimulated neither by the reduction in ionic strength nor cell swelling but by the reduction in external osmolali tY* The increased taurine release induced by hyposmolar solutions is antagonized by the diuretic furosemide (720, 721). This raises the seductive idea that the osmotic actions of taurine are related to its effect on Clflux. However, this requires further investigation. The effect of K+ on taurine release has generated considerable confusion, perhaps because of the failure to make a distinction between a cause and an effect. Exposure to high K+ concentrations depolarizes excitable cells, and there is a tendency to equate the response with the cause and to assume that any consequence of high K+ treatment is due to depolarization. In fact, K+ produces many effects, including stimulation of energy metabolism, glycogenolysis, and alterations in cyclic nucleotide concentrations, protein phosphorylation, and protein synthesis (77,179,258,461,712). Potassium also induces cell swelling (354, 798, 799). In many systems, K+-evoked release of taurine appears to be related more to the increased Cl- flux than to the depolarization. Chloride flux is accompanied by the passive entry of water. Potassium-evoked release of taurine from synaptosomes and cerebellar granule cells is Cl- dependent, the substitution of gluconate for Cl- preventing K+-evoked release (663, 684). Gluconate also prevents the synaptosomal swelling accompanying K+induced depolarization in Cl-containing media. Potassium-evoked release of GABA, on the other hand, is unaffected by Cl- or hyperosmolar conditions. In cerebellar cortical neurons, however, Cl- removal only mildly attenuates K+-induced release of taurine (684). Cultured astrocytes in isosmotic media swell in proportion to the


January

1992

PHYSIOLOGICAL

ACTIONS

K+ concentration of the media. However, the volume increase is abolished in low Cl- media or in hypertonic media. The release of taurine is proportional to the degree of swelling rather than to the concentration of K+ (604). Similarly, the K’-induced swelling of chick retinas is prevented by omission of Cl-, as is the increased release of taurine (146). The osmotically induced release of taurine is not achieved by reversal of active transport. The importance of Cl- is shown by the finding that inhibitors of Cl--HCO, exchange block release of taurine (364). Release is also, however, dependent on operation of the Na+-H+ exchanger (722). Cell acidification leads to swelling. This occurs in Cl-free medium in which there is an outflow of Cl- from the cell. Thus the Cl- dependence of osmotically released taurine may be, to one degree or another, a response, in fact, to a cellular pH shift. Potassium-evoked release of taurine occurs at K+ concentrations below those at which the release of glutamate or GABA is affected (497, 723), i.e., at nondepolarizing concentrations of K+. Taurine efflux is stimulated by K+ from glial cells also (497). Release occurs even if nondepolarizing concentrations of K+ are used but not with depolarizing concentrations if a hyperosmolar buffer is used. Compared with depolarization-induced release of amino acids, K+-evoked release of taurine is slower, of lesser magnitude, and continues after K+ concentrations have been normalized (214,270,390392, 396,448,497, 593, 627, 718). All of this is consistent with K+-evoked release of taurine being primarily an osmotic response to the Cl-induced cell swelling rather than a depolarization-induced response. A lack of dependence on Ca2’ under certain circumstances of K+-evoked release of taurine also suggests release is not neurotransmitter like (113, 177, 238, 269, 399,422,498,508,593,604,630,701). It has been claimed that taurine release from cerebellar neurons is Ca2’ dependent at 40 mM K+ but Ca2’ independent at higher K+ concentrations (619). However, others have shown that K+-induced release of taurine from cerebellar granule cells is a function of cell swelling rather than of Ca2’ (619,620). Taurine release is inhibited by Mg? Thus the decrease in taurine release seen when Ca2’ is replaced with 10 mM M$+ (619) is probably due to M$+ inhibition rather than Ca2+ dependency. This may explain why the Ca2+-channel antagonist nifedipine is without effect on the K+-evoked release of taurine from cultures of cerebellar astrocytes, although replacement of Ca2’ by M2+ leads to an inhibition of release (620). The adenosine 3’,5’-cyclic monophosphate (CAMP)induced increase in taurine transport and taurine efflux is independent of Ca2’ (34,283,498,701). It is, however, inhibited by increased osmotic pressure (498). Confusingly, in cultured cerebellar astrocytes, K+-evoked release of taurine is inhibited by dibutyryl CAMP (618). Excitotoxic amino acids produce cell edema due to stimulation of Na+ entry through voltage-activated channels followed by passive entry of Cl- and water (99, 657). Such amino acids have also been well established to increase efflux of taurine from excitable cells (79,339,

OF

113

TAURINE

390, 439-442, 445, 446, 518, 788). The taurine-releasing effect of the agonist quisqualate is completely osmotically sensitive, being abolished under hyperosmolar conditions (519). The action of kainate is partially osmotically sensitive, whereas the action of N-methyl-Daspartate is unaffected by osmolarity. Thus excitatory amino acid-induced release of taurine appears to be partially due to cell swelling and to be partially osmotically insensitive. N-methyl-D-aspartate-induced release of taurine is reduced in the absence of Ca2’ (439), as is neuronal cell death produced by this excitotoxin (206). At least for N-methyl-D-aspartate, the effects are receptor mediated, as the receptor antagonist 2-amino-5phosphonovalerate abolishes the induced release of taurine (518). A problem with many of the studies on taurine efflux is that they measure the release of preloaded [3H]taurine (364, 497, 663). What in fact is being measured in such an experiment is an increase in cell permeability, and, in the absence of other measurements, from the measurement of radiolabel one cannot be sure of the direction of mass transfer. However, in one of the few studies in which a direct comparision has been made, a good correlation was found between the K+-evoked release of preloaded [3H]taurine and endogenous taurine from mouse brain slices, except for a more rapid attenuation of release of the labeled taurine (554). Another lesson from release experiments is that different cell types respond differently to various stimuli. To avoid confusing oneself and others, therefore, it is important to use well-defined preparations. On the other hand, it is also important to remember that cells in culture may not behave the same as they do in situ. The importance of taurine in osmoregulation helps explain the ubiquity of its distribution in a way other putative functions, such as that of neurotransmission, do not. Furthermore, a primary osmoregulatory function also explains the absence of taurine (or the low amounts) in the walled cells of the bacterial and plant kingdoms. 3. Conclusions

on taurine

and osmoregulation

1) The biophysical and biochemical properties of taurine make it an excellent candidate for osmoregulation. 2) Taurine is a major osmolyte in marine invertebrates and fish. The importance of taurine as an organic osm olyte, however, varies wi .th species. Depend .ing on the species, other osmolytes assume greater or lesser importance. 3) Osmotic stress in mammalian tissues leads to large changes in taurine concentrations. As organic osmolytes are quantitatively less important in mammals, changes in taurine concentrations per se are insufficient to osmoregulate cells. To establish an osmoregulatory function in mammals, it is necessary to show that taurine affects either water movement or ion fluxes sufficiently to restore osmotic equilibrium across the cell membrane.


114

R. J. HUXTABLE

0.5

1.0

0

10

m&l,

Bullfrog Read et

heart al. (ISSO)

0

10

mM,

Guinea Khatter

pig heart et al. (lQ81)

A

4,

20

mM Guinea Franconi

2.0 Calcium

Concentration

Volume

et

pig ventricle al. (1982)

72

FIG. 9. Dependence on Ca2’ concentration of inotropic response to taurine. Three independent studies are summarized. Shown are transformations of original data from Refs. 183, 362, 643. Lower the Ca2’ concentration, greater the inotropic response to taurine. At supranormal concentrations of Ca2+, positive inotropic response to taurine disappears or is reversed to negative inotropit response.

2.8

(mM)

B. Calcium Modulation

There is considerable evidence that taurine modulates many Ca2+-dependent processes (296,297,3X& 327, 330,419,534,538,584,594). This is most clearly shown in the heart where the contractile response is a function of the rate and extent of entry of extracellular Ca2’ during the plateau phase of the action potential and where relaxation is a function of the rate and extent of removal of cytoplasmic Ca2+. The contractile responses serve, therefore, as Ca2’ detectors. The Ca2’ modulatory actions of taurine in the heart have been reviewed (315, 327).

Interest in the cardiac actions of taurine has been high since the seminal work of Read and Welty (644, 806) 30 years ago. Taurine has a plenitude of effects on the heart that appear to be Ca2’ related. It has been well established that taurine is positively inotropic in hearts exposed to subphysiological concentrations of Ca2’. Conversely, taurine is negatively inotropic in hearts exposed to supraphysiological concentrations of Ca2+ (183, 186, 187, 362, 804; Fig. 9). Taurine affords protection against the Ca2+ paradox (402), Ca2+-overload cardiomyopathy (33, 804), and arrhythmogenesis (94, 326, 644, 747, 805). Taurine also antagonizes the negative inotropy of Ca2’ channel antagonists. The Ca2+ paradox is of particular interest. Hearts exposed to Ca2+- free conditions for more than a few minutes suff er severe damage when reexposed to physiologitally normal con centrations of Ca2’ (hence the paradox). During the Ca2’ -free period, Ca2’ bound with high affinity to sites on the sarcolemma leaks away. This high-affinity Ca2’ pool holds together the inner and

outer laminae of the sarcolemmal glycocalyx. The inner lamina of the glycocalyx consists of a glycoprotein integrated with the plasma membrane and joined to the outer lamina by the cross-linking of sialic acid residues with Ca2’ (188). As the Ca2+ pool becomes depleted, the two layers separate, forming blebs and impairing the barrier to Ca2+ movement. In the subsequent presence of physiologically normal concentrations of Ca2+, too much Ca2+ reaches -the external aspect of the bilayer cell membrane and too much enters. The observation of greatest significance is that taurine is protective even if only present during the reperfusion period, i.e., after the membrane damage has occurred. It is, therefore, not affecting the degree of damage but is ameliorating the consequences of this damage. This is a similar phenomenon to that observed in skeletal muscle sarcoplasmic reticulum following phospholipase C treatment. This cleaves off the charged headgroups of phospholipids and leads to a diminution in the Ca2’ binding and transporting capacity of the organelle. Taurine antagonizes the diminution in the Ca2’ handling capacity without affecting the degree of headgroup hydrolysis by phospholipase C (300). A related phenomenon is the oxygen paradox. Reexposure to normal oxygen concentrations after a period of hypoxia leads to enzyme leakage, Ca2+ overload of the cell, and ventricular arrhythmias. Taurine protects against all these consequences (185). Taurine also protects against the sh ortening in the plateau phase of the cardiac slow action potential produced by anoxia or hypoxia, apparently by protecting against the inactivation of Ca2+ channels (669). More recently, relaxation times and contraction du-


January

1992

PHYSIOLOGICAL

ACTIONS

ration have been found to be significantly prolonged in papillary muscle of hearts taurine depleted by means of guanidinoethane sulfonate (428). This is a consequence of a prolonged plateau phase of the action potential, i.e., a prolonged Ca2’ entry phase. In congestive heart failure, there is an increase in cardiac taurine content (301). The increased taurine load derives from transport and not biosynthesis and is due to an adrenergic stimulation of taurine influx (103, 283, 303). Congestive failure is usually the consequence of a prolonged period of cardiac overload, during which there has been high adrenergic tone. The adrenergic stimulation of transport is, in turn, mediated via an increase in CAMP concentrations but is not due to an altered ion flux produced by the cyclic nucleotide (34). There is a cardiotonic action of taurine in experimental congestive heart failure, produced in rabbits by damaging the aortic valve (40). Taurine, given orally, had an inotropic action and reduced mortality. Taurine has been claimed to be of benefit in the treatment of congestive heart failure in humans, either by itself or as an adjunct to digitalis therapy (37-39, 749). It is now used for this purpose in Japan. Taurine has been claimed to be of benefit in patients resistant to therapy with digitalis and diuretics (36). The inotropic actions of digitalis are due to an increased rate and amount of delivery of Ca2’ to the myofibrillar contractile proteins. Presumably taurine, by whatever mechanism it acts, is achieving the same result. However, the cardiac actions of taurine are not mediated via the ,&adrenergic receptor (187, 667), the histamine H, receptor (187), changes in CAMP concentrations (667), or the Na+-K+-ATPase enzyme (9). The common dilated cardiomyopathy seen in house cats is associated with low concentrations of taurine in the circulation (628). Supplementation of animals with taurine prevents or reverses the development of disease. Low taurine concentrations are also associated with dilated cardiomyopathy in the fox (524). The taurine derivative taumustine, or Z-bis-(Zchloroethyl)aminoethane sulfonic acid, is an antitumor agent having a number of toxic side effects. Taurine does not affect the antitumor action but decreases the neurotoxicity and pulmonary embolism associated with taumustine (623). Both these phenomena are Ca2’ related. Thus the decrease in embolus formation may be due to a modulation of Ca2+ availability in platelets. Although the brain has not been as well studied as the heart from this regard, a number of the central actions of taurine appear to be Ca2’ related. These include the anticonvulsant actions (231, 331, 588) and interactions with opiates (118, 333, 334, 827). The excitotoxininduced release of taurine may protect cells from Ca2’ toxicity independent of an osmoregulatory function (439, 519). However, Lehmann (436) found that taurine did not modify the toxicity of N-methyl-D-aspartate. I. Calcium binding and transport: general comments

Extracellular Ca2+ concentrations are in the millimolar range: -2.4 mM in plasma and -1 mM in inter-

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stitial space. Free cytosolic Ca2’ concentrations are 103lo6 times less. Hence high-affinity binding and transport of Ca2’ [i.e., dissociation (&) or Michaelis constant (K,) in the PM range] are physiologically relevant only within the cell for extrusion of Ca2’ or transport into cell organelles. Low-affinity processes (i.e., K, or K, in the mM range), on the other hand, are relevant only for binding to the outside of the cell, for transport into the cell, or for similar processes within cell organelles such as mitochondria or sarcoplasmic reticulum in which high Ca2’ concentrations can accumulate. Calcium entry into the cell proceeds down a concentration gradient and does not directly require energy (although channel entry requires channel activation). Calcium removal from the cytoplasm proceeds against a concentration gradient and, directly or indirectly, requires energy. Entry into the cell occurs through voltage- or receptor-regulated channels or via exchange processes, such as Na’-Ca2’ exchange. Voltage-operated channels are phosphorylated by CAMP-dependent or phospholipid-dependent protein kinases (405). Receptor-operated channels have been poorly studied but appear to be opened by 1,4,5-inositol triphosphate, itself the product of a kinase (635). Both kinds of channels, therefore, have an indirect energy requirement in that ATP is used as a substrate by the kinases involved in their regulation. Movement of Ca2’ from the cytosol requires a Ca2’ pump, such as the ones present in mitochondria, sarcoplasmic reticulum, or the cell membrane. These various processes involved in Ca2’ movements are quite different, and in considering the actions of taurine on Ca2’ movement, one must be aware of which process is being affected. The Ca2+-modulatory actions of taurine involve either or both a modification of Ca2’ availability to systems sensitive to Ca2’ or a modification of the sensitivity to Ca2+, i.e., there is an alteration in intensity of either the signal or the response. Changes in signal intensity include alterations in the rate and amount of change in cytosolic Ca2’ concentrations during excitation-contraction or excitation-secretion coupling. Changes in response intensity include alterations in affinity of Ca2+ -binding sites on troponin or calmodulin or alterations in Ca2+ dependence of myosin ATPase and other Ca2+-dependent ATPases. Current evidence indicates that the major effect of taurine involves an alteration in Ca2’ delivery (104, 315, 729). The possibility of direct chelation of taurine and Ca2+ has been refuted by elegant 13C-nuclear magnetic resonance (NMR) studies (144, 145, 324). The action of taurine on Ca2+ movements thus appears to be indirect. The question reduces itself to in what way and under what conditions does taurine alter the membrane binding and transport of Ca2’. 2. Eflects of taurine on calcium, wzovements

At first sight, the actions of taurine on Ca2+ movements appear confusing and inconsistent. However,


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these actions can be largely rationalized if careful consideration is given to the preparation employed and the incubation conditions, such as the Ca2+ concentration, composition of buffer, and presence of energy source. Furthermore, most studies employ radiolabeled 45Ca2+ to follow the movement of Ca2’ from one compartment to another. Movement of radiolabel does not necessarily mean that mass transfer is occurring in the same direction, i.e., increased 45Ca2+ uptake from cytosol to mitochondria may reflect an increase in mitochondrial permeability such that the gross movement of Ca2’ is outward from the mitochondria. That taurine has marked effects on the kinetics of Ca2’ in whole tissue has been shown by a number of investigators. Rat hearts perfused with 2.5 mM 45Ca2+ for 15 min retained more radioactivity in the presence of 8 mM taurine (104). During a Z-min Ca2+-free washout, more radioactivity effluxed from the taurine-exposed hearts; however, more remained in the heart at the end of the washout. Similar observations have been made on guinea pig heart (143). Taurine also increases the absolute content of Ca2+ in guinea pig ventricular strips superfused at low Ca2+ concentrations (183, 186). At Ca2’ concentrations of 22.7 mM, however, taurine lowered the Ca2+ content of strips (183). Here, in the absence of taurine in the superfusate, the taurine content of the strips declines. One action of taurine in the superfusate, therefore, is to maintain tissue levels of taurine. Calcium transport in the submillimolar range can be considered high-affinity transport. Typically, highaffinity transport is studied in the range of 5-20 PM. High-affinity uptake of Ca2’ from the cytosol in the presence of ATP, bicarbonate, and Na+ is stimulated by taurine (231,412,457,465,466,469,475,584,599,691). In membranes as diverse as cardiac sarcolemma, retinal rod outer segments and disk membranes, and brain synaptosomes and mitochondria, taurine is without effect in the presence of ATP but in the absence of bicarbonate. For example, in rod outer segments in bicarbonate buffer, a basal Ca2’ uptake of 0.4 nmol/mg protein was increased to 3.9 nmol/mg protein in the presence of ATP (599). In the presence of ATP and taurine (25 mM), there was a further increase to 8.2 nmol/mg protein. Uptake was energy dependent in that it was M$+ dependent (i.e., suggesting the involvement of a M$+-dependent ATPase), and nonhydrolyzable analogues of ATP were without effect. Other workers found that taurine increased both the uptake and release of Ca2’ in bicarbonate-ATP buffers (412). If bicarbonate was replaced by tris(hydroxymethyl)aminomethane (Tris), neither process was affected. This suggests that, in the presence of bicarbonate, taurine is increasing the pool size of exchangeable Ca2’ in the preparation. High-affinity uptake of Ca2+ in retinal synaptosomes is inhibited by mitochondrial metabolic inhibitors (469). This suggests that this frequently studied process in synaptosomal preparations is in fact occurring in the contaminating mitochondria. This makes excellent sense in the light of the discussion demonstrat-

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ing the lack of functionality of inward-operating Ca2+ pumps in exterior membranes. The absence of the mitochondrial marker enzyme cytochrome oxidase from rod outer segments showing ATP-dependent Ca2’ transport has been interpreted as indicating the preparation was not contaminated with mitochondria (599). However, the mitochondrial inhibitors ruthenium red, oligomytin, and dicyclohexylcarbodiimide all inhibited the effect of taurine in this preparation. Others have also shown that the taurine stimulation of Ca2+ transport is inhibited by these mitochondrial agents and also by the mitchondrial inhibitor atractyloside (469). Mitochondria are much more active in transporting Ca2’ than are purified synaptosomes (419). The lower the Ca2’ concentration, the greater the activity of mitochondria relative to synaptosomes, a transporting ratio of 14:l being seen at 10 PM Ca2’. In most cases, therefore, it is safe to assume that, regardless of the preparation, high-affinity transport of Ca2+ is occurring into a subcellular organelle. Typically, bicarbonate-dependent stimulation of Ca2+ transport is observed employing 50 mM bicarbonate and 10 PM Ca2’ (412,469) or 25 mM bicarbonate and 20 PM Ca2’ (599). These buffers are supersaturated with regard to Ca2’ salts, as is made apparent by salt precipitation if the buffers are stored for l-2 days. Bicarbonate exists in aqueous solution in equilibrium with carbonate, the pK, for bicarbonate being 9.75. The solubility of calcium carbonate is -0.15 mM. Thus the solubility of Ca2’ is Na+ > K+ Yes No No

Ca2+ > Na+ > K+ Yes No No

SL, rat heart sarcolemma; P,B, rat brain synaptosomes. data from Refs. 296, 316, 317, 691, 692. * Heterogeneous lipid vesicles containing cholesterol. t Homogeneous dylcholine vesicles. $ Homogenous phosphatidylserine

Original phosphophosphativesicles.

independently found a similar low-affinity binding site on cardiac sarcolemma, showing positive cooperativity and Na+ inhibition. All these binding characteristics were reproducible in phospholipid vesicles lacking protein (Table 4). From this it can be reasonably concluded that the low-affinity binding site for taurine present in biological membranes is phospholipid in nature. Binding affinity is increased by the addition of cholesterol to the liposome, i.e., it is affected by membrane fluidity. In mixed vesicles, the addition of 50% cholesterol increased affinity from 64 to 29 mM. In vesicles prepared from single classes of phospholipids, the highest affinity of binding was found with the neutral phospholipids. Insignificant binding occurred to phosphatidylinositol (316). These binding affinities are in keeping with the structural analogy between taurine and the charged headgroups of the neutral phospholipids (Fig. 10). Taurine may form a low-afi nity charge complex with neutral phospholipids thereby altering in membranes, membrane architecture, fluidity, and properties. As cations antagonize the binding of taurine, this implies that association with the phosphate grouping is of more significance than association with the amine grouping of the phospholipid headgroup. The effect of taurine on membrane Ca2’ binding has been explained in terms of an increased affinity of Ca2+ binding with a decreased B,,, of binding. However, negative cooperativity of taurine on Ca2’ binding would produce an equivalent shift. The two situations are described by different mathmatical models: the first, binding = B,,,/[l + (K&S)], and the second, binding = B,,,/ [l + (Kd/S)nl (w here S is substrate concentration and n is the Hill coefficient). However, the underlying mechanism is not necessarily different. Taurine itself binds with positive cooperativity, implying that the binding of a taurine molecule to a given site increases the probability of an adjacent site being occupied relative


January 19%

PHYSIOLOGICAL

0 A R-0-f-OCH,~HNH, OQ

0

B

C

o=h4,CH,NH, I 0”

0 R-0-bOCH,CH,NH, I Oe

ACTIONS

0 co:

0

8

FIG. 10. Type structures for phosphatidylserine and phosphatidylethanolamine (C), illustrating taurine and charged headgroups of phospholipids.

(A), taurine similarity

(B), between

to a nonadjacent site. The binding sites for Ca2’ and taurine mutually compete inasmuch as taurine modifies Ca2+ binding and Ca2’ antagonizes taurine binding. The effect of taurine on Ca2+ binding can be well described by a curve of the following type: binding = B,,,/[l + (Kd/S)n], where n < 1, i.e., where there is negative cooperativity. In one experiment, for example, the effect of taurine on Ca2’ binding to brain synaptosomes could be described either by a fit to the two-compartment model binding

= Bmaxl 41

+ Wd11s>I+ %,x241

+ Wd 21s >I

with a residual mean square of 0.063 or by a fit to a one-compartment negative cooperativity model with a residual mean square of 0.037. In other words, excellent fits are obtained with both models, but the fit is better with the cooperativity model. The best fit was obtained with a Hill coefficient of 0.80 t 0.02. Thus a negatively cooperative effect of taurine on Ca2+ binding may be the obverse side of the coin to a positively cooperative effect on its own binding, i.e., these two effects are part and parcel of the same phenomenon. This, however, is a tentative suggestion. It appears, therefore, that the Ca2’ modulatory site is a low-affinity taurine-binding site on neutral phospholipids. The affinity for taurine is in the range of intracellular concentrations of taurine, so this site is physiologically relevant only within the cell. At low cytoplasmic Ca2’ concentrations (low PM), taurine increases the amount of phospholipid-bound Ca2+. However, the effect of taurine is antagonized by Na+ and Ca2’ itself. As the concentrations of these cations increase during the depolarization phase of the action potential, so taurine is displaced from the membrane, resulting in a decrease in the binding affinity of Ca2’ and an accelerated release of Ca2’ into the cytoplasm. Sodium also competes for binding with Ca2’, so a rise in Na+ due to the opening of the fast Na+ channels also increases the release of Ca2’ from membrane binding sites. Conversely, as cvtoplasmic Na+ and Ca2+ concentrations fall during

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repolarization, there is a rebinding of taurine to the membrane resulting in a greater affinity of binding of Ca2+. The overall effect would appear to be accelerated rates of both the onset and offset of Ca2+-dependent phenomena, such as excitation-contraction and excitationsecretion coupling. The above sequence is in part speculation and in part based on biochemical observation. It is in keeping with the known pharmacological actions of taurine and provides the beginnings of a rational basis for understanding the physiological importance of this singular amino acid. A glycoprotein binding taurine with low affinity has been isolated from heart (101, 410). This has been postulated to be involved in the cardiac actions of taurine. The binding of taurine shows positive cooperativity. Hypotaurine is a potent inhibitor of taurine binding, whereas @-alanine is without effect. This mimics the effect of th.ese analogues on the phospholipid lowaffinity binding site. Equimolar guanidinoethane sulfonate reduced taurine binding to 29%, whereas this analogue reduces low-affinity binding to the sarcolemma by only 7% (692). Thus we have a situation in which reconstituted phospholipid vesicles and a glycoprotein isolated from the sarcolemma both exhibit taurine-binding properties remarkably similar to those of the low-affinity site on the sarcolemma. We can either accept that two low-affinity sites showing positive cooperativity and having the same structure-activity requirements reside on the sarcolemma or that the glycoprotein and phospholipid sites are one and the same. If the latter, then it must be concluded that the phospholipid site has the better claim, because we can be sure that the liposomes contain no protein. A high-affinity taurine-binding site has been located on the sarcoplasmic reticulum, exhibiting a Kd of 3.2 PM (636). It is difficult to ascribe significance to such a site when intracellular taurine concentrations are 103IO4 times higher. The effect of taurine is part of a four-way interaction: taurine binds primarily to neutral phospholipids in a low-affinity process, Ca2’ binds solely to acidic phospholipids in a high-affinity process, and the binding of taurine modifies Ca2+-binding sites so as to reduce the number of sites and to increase the affinity of the remaining sites. Phosphorus-31 NMR studies on the binding of paramagnetic cations to phospholipid vesicles support the existence of a taurine-cation-phospholipid interaction (296). In keeping with this, verapamil decreases the low-affinity binding of taurine to the sarcolemma in parallel to its antagonism of the taurine-induced increase in binding affinity of Ca2+ (101). There is a hydration shell around the polar headgroups of membrane phospholipids. Removal of this hydration shell alters the phase transition temperature and other membrane properties, such as Ca2’ transport (121). The low-affinity binding of taurine may perturb this shell. The binding of taurine may also decrease the packing densitv of headgroups and the strength of the


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van der Waals interaction between lipid chains, as has been observed for the interaction of trehalose and phospholipids. We can speculate that the direct effects of taurine on phospholipid membranes modify other lipid-dependent phenomena, such as the operation of ion channels, the regulation of membrane-bound enzymes, and protein phosphorylation processes. Many membrane protein functions are modified by their lipid environment. For example, ion pumps and Na+-K+-ATPase are strongly affected by cholesterol (833). If various cell phenomena are strongly affected by the interactions of phospholipids and taurine, then one might expect some correlation between membrane phospholipid composition and cytosolic taurine concentrations. Indeed, this might be the basis for the wide variation in taurine concentrations of excitable tissues, both between species and at different developmental stages within a species. Thus the rat heart contains 35 pmol/g wet wt of taurine, but the cow heart contains only 4 pmol/g wet wt (285). The rat brain at day I of age contains 18.6 pmol/g wet wt of taurine, whereas at 56 days of age it contains 4.9 pmol/g wet wt (304). Synaptosomes of developing brain represent a good system in which to examine for correlations, since development is accompanied by large changes both in taurine content and in phospholipid composition. Taurine concentrations in the synaptosome fall from 181 nmol/mg protein on day 1 of life to 31 nmol/mg protein on day 56 (304). A strong negative correlation was found between taurine concentration and the ratio of phosphatidylethanolamine to phosphatidylcholine in the membrane (304; Fig. 11). Furthermore, synaptosomal taurine concentrations also correlate with the rate of phospholipid methylation, a process that converts phosphatidylethanolamine to phosphatidylcholine (P. Lleu and R. J. Huxtable, unpublished observations). During development, there is also an alteration in the transport and diffusion characteristics of brain membranes. The possibility is being investigated that the altered taurine concentrations are due to altered transport and diffusion through the membrane, which in turn are a simple function of the phospholipid content. Phospholipid composition is well known to affect the activity of membrane proteins, including transport proteins, and the ability of molecules to diffuse through the membrane is also affected by phospholipid composition. Increased incorporation of polyunsaturated fatty acids into cell membranes of neuroblastoma cells led to marked increases in the Vmax for glutamate transport and a smaller increase in the Vmaxfor taurine transport (43). Guinea pigs maintained on 0.4% taurine in drinking water showed a marked decrease in hepatic phosphatidylcholine content (82). The effect of taurine on membrane transition temperature may also be a consequence of phospholipid interaction and altered membrane fluidity (467). The alterations in Ca2’ transport and in Ca2+-stimulated ATPase activities in taurine-depleted hearts are not rectified by incubation with taurine (239). This

Volume 1.000

-

; 0.925 .5

-

.-0 -6 OL

5 h; 0.850 .F 0 50.775 c 13 -c zl 0.700

7.2

-

-

f 0

I 50

I 100

Taurine (nmol.mg

-’

I 150

I 200

Concentration Synaptosomal

Protein)

FIG. 11. Correlation of taurine concentration and ratio of neutral phospholipids in synaptosomal P,B fraction of developing rat brain. [From Huxtable et al. (304). Reprinted with permission by Pergamon Press.]

points to a structural change in the cell membrane, perhaps in the phospholipid composition. N-methyl-D-aspartate-induced release of taurine in the brain is Ca2+ dependent, and release is reduced in the absence of Ca2’ (439). It is possible that Ca2+ antagonism of phospholipid binding of taurine is involved in the release of taurine. With this phenomenon, as with so many others, there is mutual “feedback” between taurine and Ca2’ in that the addition of taurine reduces Ca2’ influx and hence the resulting taurine release. Phospholipid vesicles and bilayer membranes fuse under osmotic swelling (110). An osmoregulatory action of taurine, therefore, indirectly markedly affects phospholipid behavior. Membrane fusion is involved in hormone and neurotransmitter release, exocytosis, and the insertion of proteins into plasma membranes. The inhibitory effect of taurine on transmitter release may, at least in part, be related to an inhibition of membrane fusion. As Ca2’ speeds the rate of membrane fusion, the Ca2+-regulatory action of taurine may also be involved. These two phenomena provide a mechanistic basis for the much discussed “membrane stabilizing” actions of taurine (284, 300). Cryoprotection, or protection of cell functions under low-temperature conditions, is a phenomenon closely related to osmoregulation. Taurine is cryoprotective in intertidal bivalves such as MytiZu,s (4729, apparently by protecting phospholipids against fusion and leakage. The binding of taurine to phospholipid headgroups affects bilayer fluidity and phase transition temperatures (467). Other actions of taurine that may involve lipid interactions include its antiaggregating effects on platelets. Platelets are highly enriched in taurine. The platelets of taurine-deprived cats are twice as sensitive to collagen-induced aggregation, whereas human platelets incubated with taurine are more resistant to aggregation (248). On raising taurine content from 2.0 to 4.2


Jarmar-y 1992

PHYSIOLOGICAL

ACTIONS

~mol/106 platelets, the threshold for aggregation increased from 0.88 to 2.12 pg collagen/ml platelet-rich plasma. Platelet activation involves the eversion of acidic phospholipids onto the outer aspect of the membrane, followed by cross-linking via Ca2’ to y-carboxylglutamate residues on various coagulation factors. It is possible that taurine is inhibiting the phospholipid changes leading to exposure of acidic phospholipids. I. Conclusions on taurine and phospholipids

I) There is a low-affinity binding site for taurine on the neutral phospholipids of the membrane, with an affinity within the intracellular range of taurine concentrations. 2) Taurine has a negative cooperative effect on the high-affinity binding of Ca2+ to phosphatidylserine, resulting in increased affinity of binding for Ca2+ and a decreased B,,,. 3) The effect of taurine on the phospholipid binding of Ca2’ is antagonized by Ca2+ and Na+. The antagonistic action of Na+ is, in turn, antagonized by ATP. 4) The Ca2+-modulatory actions of taurine are manifested, at least in part, via the low-affinity binding site for taurine. D. Protein Interactions

Given the ubiquity of taurine in mammalian cells and the high concentrations which obtain, it is not unreasonable to expect to find taurine-dependent phenomena involving interactions with proteins. Indeed, taurine has a plethora of effects that might be the consequence of protein interactions, including the neurotransmitter-like effects. Protein interactions could be indirect, secondarily to alterations in the lipid environment produced by the lipid binding of taurine, or direct, involving the binding of taurine to protein. Effects could result from the antagonistic actions of taurine, i.e., its binding blocking the binding of a biologically active ligand, or from the agonistic actions of taurine, the binding of taurine producing some direct consequence. The sticking point in investigations in this area, however, is that such protein binding of taurine has yet to be unambiguously demonstrated. Extracellularly, binding affinities must be within an order of magnitude of the measured taurine concentrations (6-20 PM) for variations in binding to be physiologically meaningful. As discussed in section IVC, taurine binding of this order that has been well characterized can be equated with the transport site for taurine. Intracellularly, for modulation of protein activity to occur, binding constants within the range of intracellular taurine concentrations are presumably required. Higher affinity sites would be permanently occupied. Such sites, however, could be involved in protein stabilization.

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Whether or not taurine is a neurotransmitter is a, question still vigorously debated. The demonstration of high-affinity Na+-independent binding sites for taurine would be consistent with this amino acid having a transmitter function. Over a physiological concentration range of taurine, no such high-affinity Na+-independent binding of taurine is observed (313,474,476,514). However, some groups have claimed the presence of such binding with affinities in the nanomolar range (385,386, 393,394,473,824). Thus 99% of the endogenous taurine was removed from mouse brain synaptosomes by a combination of multiple freezings, thawings, washings, and detergent treatments (394). Sodium-independent binding of taurine was demonstrated in this well-pummeled preparation having a Kd .of 0.11 PM and a B,, of 0.13 pmol/mg protein. Binding occurred with positive cooperativity (388,394). This affinity may be compared with the extracellular concentrations of taurine in the brain as determined by microfiber dialysis. Depending on the brain region, these range from 6 to 20 PM (235,451). At a concentration of 6 PM taurine, >98% of the binding sites will be occupied. If positive cooperativity with a Hill coefficient of 2 is assumed (393), then the proportion of sites occupied increases to 99.97% {i.e., binding = B,,/ [1 + (KJS)‘]}. F rom the binding constants (388), it is possible to estimate that t0.001% of the taurine in the brain can be bound to Na+-independent sites. Others have found even higher affinities, up to 0.027 PM (824). Typically, Na’-independent binding for GABA is lo-100 times more abundant (473). Corresponding affinities for GABA are 1.2 PM for Na+ dependent and 0.37 PM for Na’-independent binding (156) compared with an extracellular GABA concentration of 0.1 PM (664). At this concentration, ~21% of the Na+-independent sites will be occupied. Thus the GABA-binding sites have neurochemical relevence not obvious for the taurine-binding sites. Sodium-dependent binding is lo-fold greater than Na+-independent binding, but freezing and thawing abolishes Na+-dependent binding while doubling Na+-independent binding (156). When taurine concentrations are depleted by means of guanidinoethane sulfonate (308), Na’-independent binding sites show increased affinity for taurine, the Kd falling from 0.54 to 0.10 PM (386). These studies show that brain membranes can be manipulated to express a low degree of Na+-independent binding of taurine (394). The physiological relevance of such binding remains to be demonstrated. Such drastic treatment of tissue is necessary for binding activity to be expressed that it is questionable whether the binding sites exist in vivo or whether they are an artifact of the treatment. If they exist, what is the relevance of sites of such high affinity that they are half saturated at taurine concentrations of -1% of those actually occurring in brain extracellular fluid (235)? The Na+-independent binding demonstrated for taurine is much less than that found for GABA (388, 394, 473,774). There is the further question, therefore, as to whether the observed binding is to sites unique for taurine or to sites that also bind GABA. Binding is blocked


124

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by the glycine antagonist, strychnine, or the GABA antagonists picrotoxin, bicuculline, and homotaurine, suggesting that binding could be to either glycine or GABA sites. The electrophysiological actions of taurine are typically explained on the basis of taurine acting at receptors for GABA, glycine, or taurine. The area has been recently reviewed (297). The relevant point for this review is how good the evidence is that these actions of taurine are mediated by protein binding. It would take a Judge Jeffreys to hang on the basis of the available evidence. Both biochemical (binding) and electrophysiological studies must concur in the demonstration of a “taurine receptor.” Taurine noncompetitively blocks the binding of GABA to postsynaptic binding sites, GABA exhibiting a decreased B,,, with no change in & (221,257,328,487489,576). This implies that taurine is not binding at the same site as GABA. It displaces the binding of GABA to both high- and low-affinity sites, with half-maximal inhibitory concentrations (IC,) of 30 and 700 PM, respectively (488, 489). Others have found taurine to be less active in antagonizing the binding of GABA (257). Taurine appears to be rather more effective at the GABAB site, having an IC,, of 5 PM (398). If taurine is capable of inhibiting GABA binding, one would imagine it should not be too difficult to demonstrate direct binding of taurine, but so far this demonstration has been elusive. Taurine also appears to modify the postsynaptic responses to GABA. A characteristic of benzodiazepine binding in the brain is that GABA stimulates binding in washed, but not unwashed, membranes. Thus GABA stimulates the binding of flunitrazepam and diazepam to the benzodiazepine-binding site on the GABA receptor-Cl- channel complex. Taurine inhibits GABA stimulation (328, 488, 490, 514). The half-maximal effective dose (ED,& concentrations found range from 7 (514) to 780 PM (488, 489). Again, the inhibition is noncompetitive (328). The antagonistic effect of taurine cannot be overcome by increasing the concentration of GABA, indicating the effect is not due to competition at the GABA-binding site (328). Here, taurine is acting as a partial agonist of the GABA-benzodiazepine receptor complex, affecting the GABA recognition site but not directly affecting the benzodiazepine-binding site. The fact that diazepam binding is increased by taurine in the presence of pentobarbital suggests that taurine interacts with the barbiturate-binding site (328). There is confusionover the action of taurine on benzodiazepine binding in the absence of GABA. Some workers find that taurine causes a reduction in the B,,, of flunitrazepam binding but an increase in the affinity (514). This parallels the action of taurine on Ca2’ binding. However, there is a difference of opinion on the dose-response relationships. The IC,, for inhibition of flunitrazepam binding has been claimed to be between 12 and 32 PM (514) and to be 30-50 mM (488,818). Thus, although it is clear that taurine interacts with the benzodiazepine-GABA-Clchannel complex, it is not at all clear how it is acting. There is a recent report that taumanner. the rine inhibits. in a bicuculline-dependent

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72

binding of the Cl- ionophore t-butylbicyclophosphorothionate to the GABA, receptor complex (638). As inhibition of binding has been correlated with the opening of the Cl- channel, the action of taurine suggests that it stimulates Cl- flux by interacting with the recognition site for GABA on the GABA* receptor complex. The available knowledge does not establish, but does not disprove, that taurine is acting at a proteinaceous site. In terms of the lipid interactions of taurine, it is noteworthy that GABA binding appears to be regulated by membrane phospholipids. Treating brain membranes with phospholipase C or glycerophosphoethanolamine increases the affinity of GABA binding (463). Furthermore, whereas taurine inhibits the binding of flunitrazepam to synaptosomes (P2 fraction) at 0-4”C, taurine stimulates binding at 37OC (638). This suggests that the effect of taurine is modified by a phase change in the membrane. The higher affinities reported in some of the papers cited are likely to be inaccurate due to a failure to take into account the release of endogenous taurine from the membrane preparations being used. It is difficult to prepare membranes free of releasable taurine, and even well-washed preparations can release sufficient taurine to raise taurine concentrations by an order of magnitude at nominal concentrations under 10 FM (313). The failure to date to demonstrate receptor binding for taurine raises the major question as to how its electrophysiological actions are expressed. These have been assumed to be mediated by interactions at protein receptor sites controlling ion fluxes. Kudo et al. (406) have proposed subtypes of taurine receptors in the frog spinal cord based on electrophysiological responses. Mathers et al. (503) have concluded that there are three types of taurine receptors in the spinal cord: depolarizing, hyperpolarizing, and glycine types. Others report that the taurine antagonist (TAG; or 6-aminomethyl-3-methyl4H,l,2,4-benzothiadiazine-1,1-dioxide) antagonizes the depolarizing actions of taurine and P-alanine in the frog spinal cord without affecting the action of glycine or GABA (582). Thus there is a degree of evidence that at least in the spinal cord there may be specific receptors for taurinelike substances. However, the demonstration of binding of the appropriate type and structure-activity requirements is an absolute requirement for validation of the existence of a receptor. Abundant reports of the neuroinhibitory actions of taurine start with the findings of Curtis and co-workers (123, 125, 126). The evidence is good both peripherally and centrally that these actions of taurine are the result of a stimulation of Cl- current (117, 226, 227, 543, 556, 559, 744). This leads to hyperpolarization of the cell membrane. The degree of hyperpolarization produced by taurine decreases as the membrane potential is made more negative. At sufficiently negative potentials, the effect reverses and taurine produces a depolarization or hypopolarization. The crossover potential is the “reversal A reversal potential occurs with taurine in potential.” guinea pig hippocampal slices at -55 to -67 mV (840), in


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PHYSIOLOGICAL

ACTIONS

guinea pig Purkinje cell dendrites at -125 mV (560), and in lobster axon at -85 mV (226). Neuronal CA3 pyramidal cells and granule cells that are syn aptically stimulated fro m resting potentials of -65 mV are hyperpolarized in the presence of taurine. At a resting potential of -80 mV, both cell types are depolarized. At -72 mV, there is a biphasic response to taurine, with an initial hyperpolarizing response being followed by a depolarizing response. The action of taurine on cerebellar Purkinje cells is similarly due to an effect on Cl- conductance. Here, however, a reversal potential of -125 mV is found (559-562). The differing reversal potentials in various preparations are due to the effect of the K+ concentration on the Cl- gradient. The hyperpolarizing action of taurine on pyramidal CA1 neurons has a reversal potential of between -65 and -70 mV (744). This is the same as for Cl-dependent responses in hippocampal slices (14, 25, 753, 754) and is positive to the K+-induced reversal potential (753, 754). Earlier conclusions that taurine directly altered K+ conductance may be in error (226,563). Recently, Okamoto et al. (559), working with Purkinje cells, concluded that the apparent dependency of the reversal potential on K+ concentration was an effect secondary to an alteration in internal Cl- concentration produced by the external change in K+ concentration. Thus an increase in K+ conductance is either absent or only a minor part of the action of taurine. A reversal of electrophysiological action is also seen at low Cl- concentrations. The taurine-induced hyperpolarization of Purkinje cell dendrites decreases the frequency of spontaneous firing (560). This inhibitory action reverses to an excitatory action at Cl- concentrations 90% of an administered dose was converted to taurine. Conversion in the guinea pig is slower, but even so, 80-90% metabolism to taurine occurs within 18 h. In vitro, the rate of conversion to taurine is strongly dependent on sulfide. An initial product is thiocysteamine. Cystamine, the oxidative dimer of cysteamine, is transported into the lung by a two-component system, one component having a K, of 12 PM and the other a K, of 503 PM (452). High-affinity transport is inhibited by the pneumotoxin, paraquat. In the lungs, cystamine is efficiently converted to taurine, apparently by a GSHdependent process, as conversion is inhibited when GSH is depleted. It has been suggested that this process protects the lu ngs from oxidative stress (452). l

l

OF

TAURINE

131

Hypotaurine oxidizing activity is found in many tissues (85, 153, 166). These include ox retina (136), rat spleen (622), and other organs (165, 550). Hypotaurine, also, is normally present only in low amounts. In the brain, for example, hypotaurine concentrations are only 1% those of taurine (611). There are two situations, however, in which millimolar concentrations of hypotaurine occur: in the regenerating liver (734, 736) and in the male reproductive system (372, 373, 516). Seminal plasma is unusual among body fluids in that its osmolarity is determined primarily by organic components. Semen is also high in unsaturated fatty acids, which require protection from oxidation. Whole semen of guinea pigs contains 26 mM hypotaurine (494). In guinea pig seminal vesicles, hypotaurine concentration is 6.3 pmol/g, and in the prostate it is 4.6 pmol/g (values in this paragraph are probably based on wet weight, although this is not stated in the cited papers) (370). Taurine concentrations are about the same. Mouse seminal vesicles contain 2.1 pmol/g hypotaurine compared with 6.5 pmol/g in the cauda of the epididymis (the cordlike structure on the back of the testes) and 5.9 pmol/g in the caput. The testes contain only 0.21 pmol/g hypotaurine, but 1.8 pmol/ml are present in seminal fluid (371). The mouse contains far higher concentrations of taurine, however, with 41.9 pmol/g being present in seminal vesicles and 47.4 pmol/ml in seminal fluid. Epididymal plasma from the cauda epididymis typically contains high concentrations of taurine plus hypotaurine. Combined concentrations are 5.2 mM in rams, 49.5 mM in rabbits, and 53.4 mM in boars (494). Concentrations ranging between lo-l6 and lo-l5 mol taurine and hypotaurine per sperm have been reported, respectively, although these numbers would be more interpretable if given per milliliter or per gram (516). Hypotaurine was absent from human acrosomes, the caplike structure on the head of spermatozoa, and may not be present in human sperm (784). Taurine, on the other hand, is one of the major free amino acids found in human acrosomes. In boars at least, hypotaurine is located in sperm rather than in seminal fluid (777). Spermatozoa are itinerant cells that must adjust to a continually changing environment in first the male and then the female genital tract. In men, it takes 2 mo for the primary spermatogonium to develop to the spermatozoon and another 12 days for the latter to pass through the epididymis. Sperm are viable in the female tract for up to l-2 days. In certain mammals, such as bats, and in many nonmammalian species, spermatozoa survive in the female tract for several months (494). In view of the susceptibility of sperm to oxidative damage and their lack of normal enzymatic protection from partially reduced oxygen intermediates, it is intriguing to speculate that hypotaurine provides a chemical defense. Mammalian sperm lack both catalase and a functional GSH reductase system (17). Although GSH reductase activity can be measured, the absence of GSH in sperm renders the enzyme irrelevant in the metabolism


132

R. J. HUXTABLE

of hydrogen peroxide. It may, however, be involved in the metabolism of lipid hydroperoxides (265). The third enzyme, superoxide dismutase, on the other hand, is present in spermatozoa (264,520). Superoxide is toxic to sperm, causing lipid peroxidation and loss of motility. Due to protonation, the rate of peroxidation increases markedly with a decrease in pH. About one-third of the superoxide is generated in the sperm mitochondria; the rest is generated in the cytosol. Mammalian sperm are rich in plasmalogens, containing vinyl ether functions that react with oxygen to generate superoxide. At 24°C rabbit sperm generate superoxide at a rate of 0.2 nmol min-l . lo* cells-l (264). In the presence of cyanide, this rate increases to 1.8 nmol. min-l IO8 cells-l due to inhibition of superoxide dismutase. The dismutase produces hydrogen peroxide. Rabbit spermatozoa make 0.8 nmol peroxide min-l lo* cells-l (265). The rate drops at cell concentrations >107/ml because of the reaction of peroxide with membrane lipids. The spontaneous inactivation of superoxide dismutase with time in ejaculated sperm correlates with the loss of motility. The susceptibility to oxidative damage of the highly unsaturated membranes of sperm is indicated by the rates of malondialdehyde formation in sperm incubated at 37OC. In Tris phosphate buffer, the rate averages 0.05 nmol h-l. IO* cells-l for many hours (18). The number of inert spermatozoa increases linearly with malondialdehyde production. Movement ceases completely at 0.05 nmol/lO* cells. Malondialdehyde inhibits motility independent of lipid peroxidation (19). Thus addition of malondialdehyde to nonoxidized sperm reduces motility. The loss of motility on storage also correlates with the loss of plasmalogen (l&346,494, 512) and degree of peroxidation (135). As superoxide is formed aerobically, the movement of sperm from an anaerobic to an aerobic environment on ejaculation represents a considerable biochemical stress (20,264). The oxygen tension in rabbit oviduct has been measured as 60 Torr (500). A small fraction of hypotaurine is irreversibly transaminated to acetaldehyde and sulfate (163, 164, 166). The enzymology of the oxidation of the remainder to taurine was for many years one of the more profound mysteries of taurine biosynthesis. Although, in vivo, hypotaurine is readily converted to taurine, on attempts to purify the responsible enzyme, activity would “softly and suddenly vanish away.” Evidence has now been obtained, however, for a radical mechanism of oxidation (165, 293). The suggested pathway involves radical intermediates formed from hypotaurine by an NADPHdependent process (Fig. 13). The oxidation involves the novel intermediacy of a disulfone, an unexpected interposition of a dimeric intermediate in a monomeric pathway (Fig. 13). Hydrolysis of the disulfone releases 1 mol taurine and 1 mol hypotaurine. The monomeric oxidation of sulfur-containing metabolites (e.g., cysteine to cysteine sulfinate to cysteate) involves oxidation states of 0, +2, and +4. However, the formation of a disulfone allows one electron oxidation of the sulfur. Thus hypotaurine, at oxidation state +2, is converted via a disull

l

l

Volume

72

‘OH

. OH @-

Lc!2rlnecliate

0 II R-S-O

/ 0

.. Hypotaurine 0

l

II

i

R-S=0 I R-S=0 II 0 Q - Disulfone

l

Taurine FIG. 13. Hydroxyl radical trap in proposed route of enzymatic oxidation of hypotaurine.

fone (+3) to taurine (+4). Hypotaurine is able to quench hydroxyl radicals generated by the xanthine oxidase system (EC 1.1.3.22) (165) in keeping with the chemical studies (28). This suggests that the free radical mechanism of disulfone formation may be related to the high concentration of hypotaurine found in male accessory sexual tissues. The disulfone has been detected in rat testes, but more work on the enzymology of its formation is required. Although experimental support has been adduced for the radical oxidation of hypotaurine (163, 164, 166), it still requires verification. The millimolar concentrations of hypotaurine in ejaculate and oviductal fluid may serve to protect the highly unsaturated membranes of sperm from the high ambient oxygen in the female genital tract (516). Hypotaurine inhibits the loss of sperm motility (19). This is a protective effect that is shared by a number of other agents, possibly acting by different mechanisms. Thus substances as diverse as epinephrine, albumin, lactate, and taurine also inhibit the loss of motility. The formation of malondialdehyde is reduced by hypotaurine in keeping with the effect on motility. Hypotaurine reduces superoxide formation in sperm, an observation at variance with the reported lack of scavenging of superoxide by hypotaurine (28). However, hypotaurine also reduces the inactivation of superoxide dismutase. As this is the prime enzymatic defense against peroxida-


January 1992

PHYSIOLOGICAL

ACTIONS

tion, this is probably an important biochemical activity of hypotaurine in ejaculated sperm (20). The protective effects of hypotaurine on peroxidation and sperm motility show markedly different potencies. Protection from peroxidation is seen at concentrations of 20.5 mM, while an effect on motility is seen in the low micromolar range (450). Taurine has similar actions on both motility and viability. At 20 PM, it maintains motility without providing protection from peroxidation (529). Hypotaurine, along with taurine, has been considered to be a sperm motility factor in hamsters and mice (49,449,516,529) but not in boars (234). Epinephrine and hypotaurine independently capacitate hamster sperm, but prior exposure of the sperm to hypotaurine is a prerequisite for the action of epinephrine (19,60,450). Capacitation is the sequence of metabolic and cellular changes whereby the sperm is prepared for fusion with the ovum. Conversely, the greatest effect of hypotaurine and taurine on motility and fertilization is obtained in the presence of the ,&adrenergic agonist isoproterenol (449). This may be related to adrenergic stimulation of transport of these ,&amino acids into the sperm, as has been found for the &adrenergic systems present in the heart and pineal (103, 810, 811). Sperm, once unmanned and wandering like the 2Marie Celeste, also encounter hypotaurine in the oviductal secretions (370). Mammalian oviductal fluids typically contain between 0.5 and 2 mM taurine plus hypotaurine (516). Flavins catalyze the oxidation of sulfinate groups to sulfonates under irradiation at 365 nm (650). Such photooxidation of hypotaurine has been proposed to be of physiological significance in the retina, a flavin-rich tissue. In summary, the protective effect of hypotaurine (and taurine) on male sexual function is complex. Hypotaurine in some of its actions is an antioxidant. Other actions it has in common with taurine, and these are presumably mediated by separate mechanisms. Possibly these mechanisms involve sperm cell osmoregulation. Oxidative damage results in osmoregulatory disturbances, loss of cell constituents, and cell death. Taurine and hypotaurine are present in seminal fluid and sperm in millimolar quantities and share the same transport system. In the brain, the process of taurine biosynthesis may be part of an antioxidant mechanism protecting neuronal membranes, while the product of biosynthesis may fulfill specific neuromodulatory and membranestabilizing functions. An otherwise “wasted” oxidation of cysteine (to P-sulfinylpyruvate and sulfate) is diverted to a biologically functional oxidation (the trapping of free radicals during the oxidation of hypotaurine). The conservation of central biosynthesis, even in species lacking the overall ability to synthesize sufficient taurine for their needs, and the greater immunity of cysteine sulfinate decarboxylase compared with glutamate decarboxylase to vitamin B, deficiency (647), suggest this remnant biosynthesis is physiologically significant. Earlv reports on the loss of cvsteine sulfinate

OF

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133

decarboxylase activity in the brains of vitamin B,-deficient animals are probably invalidated, or at least confounded, by the high substrate levels used. Under such conditions, the bulk of cysteine sulfinate decarboxylation is, in fact, being performed by glutamate decarboxylase, as discussed in a recent review (297). The regenerating liver is another system in which relatively enormous amounts of hypotaurine are found (734). From undetectable concentrations in normal livers, up to 3 pmol/g wet wt may be found within 4 h of partial hepatectomy. The functional significance of this is unknown. Myeloperoxidase (EC 1.11.1.7) oxidizes the sulfur in N-acetylcysteine and N-acetylcystine to sulfonate (149). The cysteic acid formed can be decarboxylated to taurine. The oxidant is Cl- and H,02 or HOC1 directly. Such a reaction serves to remove oxidizing intermediates, as discussed in section VIA. I. Conclusions on antioxidation

by taurine precursurs

1) Cysteamine and hypotaurine are readily oxidized, both enzymatically and chemically, to taurine. 2) Hypotaurine may be oxidized enzymatically to taurine via the intermediacy of a disulfone. The oxidation process may serve as a radical trap of hydroxy radicals. 3) Hypotaurine reduces malondialdehyde formation, an index of peroxidation, from lipids. 4) Hypotaurine concentrations are high in the male reproductive tract where it may function as an antioxidant, protecting the highly unsaturated membranes of spermatozoa. B. Radioprotection

Antioxidative and radioprotective mechanisms are related inasmuch as both involve interruption of free radical propagation reactions and detoxification of partially reduced oxygen intermediates. However, whereas a relatively small number of investigations have examined the physiological actions of hypotaurine as an antioxidant, a large body of work has been devoted to the pharmacology of cysteamine as a radioprotective agent. Cysteamine and its simple derivatives comprise the most potent radioprotectors yet found. As discussed in section VA, mammals readily oxidize cysteamine to hypotaurine, and on to taurine, by means of the enzyme cysteamine dioxygenase (EC 1.13.11.19) (8889). However, little cysteamine is formed endogenously. The study of the protective actions of cysteamine and related thiols against ionizing radiation began with the nuclear age. From the 1950s onward, an immense amount of research was conducted in the United States, Europe, and the Soviet Union. Water is the most abundant constituent of cells. The initial changes caused by ionizing radiation involve the radiolvsis of water (793). The initial step in radioly-


134

R. J. HUXTABLE R’ eaq

+SH-

B

RS’ + Hz0

C

RS’+H2

D

_/-‘OH

RSH

. H’

R’ + H2S E

c

FIG. 14. Radical trapping by thiols of products of radiolysis of water. Reaction A is preferred reaction for most thiols with hydrated electron. Reaction D is preferred for reaction of hydrogen radical with primary amines.

sis can involve either ionization or electronic excitation. The latter process involves the transfer of insufficient energy to a water molecule to remove an electron completely. Instead, the electron is raised to a normally unoccupied outer orbital. The solvolysis of water yields three radicals: hydroxyl, hydrogen, and the solvated electron. Hydroxyl and hydrogen are scavenged by organic substrates within the cell, initiating the biological damage that is a consequence of exposure to ionizing radiation. Hydroxyl is a strongly oxidizing species. Because the O-H bond is stronger than the typical C-H bond, carbon-bound hydrogen is abstracted indiscriminately. Both the solvated electron (e;J and the hydrogen atom independently react with oxygen to form peroxyl radicals (superoxide) e&+0,+0,’

(3)

He +O,+HO,e

(4)

The formation of superoxide by reaction of the primary radiolytic products of water with oxygen is a major reason why ionizing radiation is biologically less damaging under anoxic or hypoxic conditions. It also suggests the close relationship between antioxidants and radioprotectants. A number of endogenous radioprotectants are found in the cell. The main ones are a-tocopherol in lipid phases and GSH and ascorbate in aqueous phases. Mechanisms by which radioprotection is mediated include energy transfer (providing a sink to absorb radiation energy), quenching of organic free radicals, and enzyme repair. Water radicals are so reactive that radioprotectants are inefficient scavengers. However, thiols react readily with all three of the primary radicals formed by radiolysis of water (Fig. 14). The thiyl radical (RS) is probably then oxidized further RS RSO,

l

+O,-,RSO,e

+ RSH + RSOzH + RS

72

The earlier literature on cysteamine can be accessed through the review of Bacq (42). Quenching, or “repair,” of target radicals (T . ) formed by radiolysis is probably a major mechanism whereby cysteamine exerts its radioprotective effects

A

RS-+H’

Volume

To +RSH+TH+-RS

(7)

To +O,-,TO,

(8)

Equations 6 and 7 are competing reactions. However, this is not the sole action of cysteamine. It binds tightly to DNA through electrostatic interactions of the amine group with phosphate residues (72, 462). Radiation-induced breaks are reduced as a result of such binding (423). Some spatial specificity is involved, since higher homologues of cysteamine, such as aminobutane thiol, have much less radioprotective capability in animals (72, 137, 222, 626). Bacteria, however, are not so discriminating with regard to chain length (119). Thiols may also protect from radiation by reoxidizing disulfide bridges of cell macromolecules inactivated by radiation. However, a significant involvement of such a mechanism does not explain the selectivity of cysteamine compared with other thiols. Thiols also react avidly with oxygen, reducing the rate of formation of peroxyl radicals. Cysteamine lowers indirect radiation effects by scavenging hydroxyl(400). For this to be significant, high concentrations of thiols are needed. The amino group of cysteamine is involved in its radioprotective activity inasmuch as acylation markedly reduces potency (137). The amino group may serve to stabilize the initially formed thiyl radical via cyclic resonance forms (Fig. 15). A transient inhibition of DNA synthesis has been reported for cysteamine in mouse liver (522). It has been suggested that this also results in a radioprotective effect. 1. Conclusion

on radioprotection

by taurine

precursors

Cysteamine is a powerful radioprotectant radical scavenging abilities.

due to its

C. Cysteine Detoxijcation Free cysteine is neurotoxic, particularly to the developing animal (573,574). The toxicity is similar to that

(5) l (6)

H

Much of the chemistry of thiyl radicals is obscure, due to the high rates of reaction and the instability of the intermediates.

H

FIG. 15. Stabilization of thiyl radical formed from cysteamine via cyclic resonance forms. Such stabilization favors radical trapping by reactions C and D of Fin. 14.


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PHYSIOLOGICAL

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seen with the excitotoxins, i.e., acidic, excitatory amino acids such as aspartate and glutamate. Damage to the developing brain from cysteine is more widespread than that resulting from the excitatory amino acids. Glutamate and aspartate are toxic to those areas having a fenestrated endothelium in their vascular beds (i.e., having a poorly developed blood-brain barrier). These regions, the circumventricular regions of the brain, include the hypothalamus, a neuroendocrine regulatory center (571, 574, 575). It has been suggested that cysteine, a nonacidic, rather lipophilic, amino acid, penetrates other areas of the brain more readily that the charged lipophobic excitotoxins. Once in the brain, cysteine appears to be excitotoxic partially due to N-carbamate formation (575) and partially due to oxidation to the acidic cysteine sulfinate (574). Cysteine is also toxic to the retina (609). Levels in excess of 1 g/kg body wt given subcutaneously to 4-dayold rats produce permanent retinal dystrophy. Ganglion cells in the retina are reduced to one-half of normal. Metabolism of cysteine sulfinate to taurine, jtherefore, could be considered a detoxification function. However, carnivores, with a high dietary intake of cysteine and methionine, in general are poor metabolizers to taurine. Furthermore, in mice, as dietary cysteine load is increased, the conversion to taurine decreases (801). Thus detoxification of sulfur amino acids is an ancillary rather than a major function of taurine biosynthesis. VI.

METABOLIC

ACTIONS:

A. Antioxidation:

TAURINE

Chloramine

AS PRECURSOR

Story

Taurine has often been suggested to have a function in protecting biological systems from oxygen, despite its lack of ready oxidizability (688, 758, 823). The free energy difference between a sulfonate group at oxidation state +4 and a sulfate group at an oxidation state of +6 is ~260 kJ/mol (294). Although the sulfonate group of taurine could, therefore, theoretically serve as a reducing agent by undergoing oxidation to sulfate, mammals lack the enzymatic machinery to facilitate such an oxidation. Chemically, taurine reacts poorly with superoxide, peroxide, and the hydroxyl radical (28). However, some intriguing observations suggest a potential function for taurine as an antioxidant by virtue of its amino group. Neutrophilic polymorphonuclear leukocytes, or neutrophils, are circulating defensive cells having antimicrobial, cytotoxic, and cytolytic activities. They release the whole armamentarium of reactive oxygen intermediates in the course of these activities (803). They generate H,Os and secrete the enzyme myeloperoxidase (EC 1.11.1.10). Substrate and enzyme react with Cl- to produce the highly reactive hypochlorite H,Oz + Cl- + H+ -+ HOC1 + H,O

(9)

Hypochlorite reacts with primary amines to form chloroamines, RNHCl, in the extracellular medium. In

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135

TAURINE

vitro, at least, one of the most reactive amines is taurine (757,802). Endogenously, this is one of the amines present in greatest concentration. Human leukocytes are reported to contain 26 mM taurine (726), and human neutrophils contain 22 mM (223). Extracellular concentrations are normally lower, averaging 50 PM in human plasma (24, 769, 789). Researchers appear undecided as to whether the N-chlorotaurine generated should wear a white or black hat, i.e., whether it is protective or toxic (223, 224, 688, 758, 803). On the one hand, the formation of mono- and dichloro derivatives of taurine has been suggested to be a protective mechanism removing the highly toxic hypochlorite. N-chlorotaurine is transported into erythrocytes by the anion transport system where it is reduced by glutathione. The released taurine is thereby “trapped” within the cell. The glutathione consumed is regenerated by glutathione reductase RNHCl

+ 2GSH --) RNH;

GSSG + NADPH

+ Cl- + GSSG

(10)

+ H+ --) 2GSH + NADP+

(11)

where GSSG is oxidized glutathione. When Equation IO is the rate-limiting step, there is no depletion of cell glutathione. At high chloramine concentrations, Equation II becomes rate limiting, and the glutathione pool is depleted. Under these conditions, other cell components react, including hemoglobin, sulfhydryl groups, and intermediates involved in energy metabolism (758). Cell lysis and death can result. Normally, however, the process serves as a removal mechanism for hypochlorite and is postulated to be a defensive strategy against oxidative damage to circulating components. The bacteriotidal action of N-chlorotaurine may also serve a biological function (756). On the other hand, in view of the toxicity of Nchlorotaurine and other chloramines, it is difficult to conceive of their formation as conferring a benefit on the cell. In effect, a highly reactive extracellular oxidant with a short half-life has been transformed into a less reactive intracellular oxidant with a half-life of 18 h (690). It rather appears as if the cell must accept the burden of removing these adventitiously formed metabolites to avoid the expression of their toxicity. Their toxic actions include dismutation to the more reactive dichloroamines (Eq. I@, reaction with ammonium ion to generate chloramine (NH&l), oxidation of iodide ion to iodine with resulting iodination of cell components, and oxidation of cell thiols and disulfides RNHCl

+ RNHCl

+ RNH,

+ RNCI,

(I@

N-chlorotaurine impairs the barrier functions of cell membranes. Cultured endothelial cells from various sources exposed to N-chlorotaurine show increased albumin flux, increased hydraulic conductivity, and decreased electrical resistance (704). Other mechanisms are also involved in the expression of antioxidant activities by taurine. Taurine has


136

R. J. HUXTABLE

protective actions on the functions of retinal rod outer segments. Membranes of rod outer segments are rich in unsaturated fatty acids and are vulnerable to peroxidative damage (66, 128, 351, 809). Between 40 and 50% of the fatty acids in rod outer segments are tetra unsaturated or greater (128). These high levels permit the degree of membrane fluidity required for phototransduction. Exposure to light increases the rate of membrane peroxidation by -50%. Both taurine and hypotaurine at the relatively high concentration of 25 mM reduce malondialdehyde formation (592). Taurine does not, however, reduce peroxidation induced by Fe2+ (590). Similarly, taurine decreases the degree of carbon tetrachloride-induced malondialdehyde formation in liver and liver microsomes (535) and scavenges superoxide radicals in rabbit spermatozoa (19). The pneumotoxic herbicide, paraquat, stimulates lipid peroxidation secondary to superoxide formation. Taurine, continuously infused, protected dogs from the acute effects of paraquat poisoning, preventing oliguria and reducing paraquat accumulation by the lung (336). Another pneumotoxic agent is the antineoplastic compound bleomycin. This produces pulmonary fibrosis, limiting its clinical use. Taurine inhibited the inflammation and the increase in lung collagen induced by bleomycin (800). Bleomycin forms an intracellular complex with Fe2+, and it has been proposed that taurine scavenges oxygen free radicals generated by the complex. A possible mechanism is the depletion of GSH caused by N-chlorotaurine preventing reduction of the bleomyciniron complex, which in turn blocks further formation of reactive oxygen intermediates. Taurine also prevents the acute inflammation and morphological alterations produced in hamster lungs by nitrogen dioxide (218). The release of prostaglandin I, from aorta and myometrium is increased by taurine both in vivo and in vitro (154). This has been suggested to be due to the protection of prostaglandin I, synthetase from the action of lipid peroxides. Retinoids have a detergent action on biological membranes, leading to impairment of function or even disruption. Taurine protects human lymphoblastoid cells in culture from retinol-induced injury (605, 606). However, taurine affords no protection from the embryotoxicity of isoretinoin in rats (5). Taurine lowers blood pressure and increases the force of cardiac contraction (increasing the change in pressure over time) in rabbits made atherosclerotic by being fed cholesterol (617). These effects of taurine are achieved without alteration in serum lipids or Ca2’. It has been suggested that taurine is acting to reduce lipid oxidation and resulting foam cell formation. Increased cholesterol intake has been shown to raise susceptibility to lipid peroxidation in red blood cells. It has been suggested that in the CNS taurine protects from hypoxia by attenuating the Ca2’ overload that normally results in cells in which energy production has been impaired (688). However, although there is a wealth of information concerning the effect of taurine on Ca2’ movements, there is no direct evidence for a

Volume

72

protective effect in hypoxia. Indirect evidence includes the finding that taurine given intracerebroventricularly protects mice from learning impairments induced by hypoxia. Taurine also protected mice from hypoxia-induced convulsions (483, 689). I. Conclusions

on antioxidation

by taurine

1) Taurine reacts with hypochlorite biologically generated from peroxide and Cl- to form N-chlorotaurine, which is reduced intracellularly to Cl- and taurine. 2) Although this process removes a powerful oxidant, the toxicity of N-chlorotaurine renders it unclear as to whether on balance the operation of this process is beneficial or damaging to the cell. 3) Taurine protects against oxidative damage under many conditions, decreasing rates of malondialdehyde formation from unsaturated membrane lipids. B. Radioprotection

by Taurine

Taurine has radioprotective abilities in both microorganisms and higher animals (138,141,376,831). In the yeast Saccharomyces ellipsoides, it increases survivability following irradiation without influencing the immediate radiation damage (52). In liver mitochondria, respiratory control and oxidative phosphorylation are maintained in the presence of taurine following gamma radiation (141). Taurine prolongs the life of %o-irradiated mice, perhaps because of its insulin-like actions (140). It also promotes leukocyte recovery in radiationexposed mice (2). Likewise, survivability of cardiomyocytes from cynomolgus monkeys is increased by taurine, while radiation-induced hemolysis of erythrocytes is decreased (376). These actions of taurine, however, are probably secondary to a membrane-stabilizing effect rather than being a direct radioprotective action. However, the radioprotectant activity of cysteamine is possibly due both to its own activity and to the protection offered by the taurine to which it is converted (302). Twelve days after exposure of rats to 700 rads, insulin-like activity in the circulation drops. Taurine restores the insulin-secreting capacity of the pancreas and normalizes carbohydrate metabolism (139). The urinary excretion of taurine increases after radiation exposure (e.g., see Ref. 2). This may be an instance of the general increase in taurine excretion following cell damage. A similar response is seen following X-irradiation, surgery, and myocardial infarction. I. Conclusion

on radioprotection

by taurine

The radioprotective actions of taurine are probably secondary to its membrane stabilizing actions, i.e., it reduces the consequence of membrane damage. C. Energy

Storage (Phosphagen)

Although ATP is the proximate source of chemical energv in the cell, its levels in mammals are maintained


January

1992

by replenishment phosphorylcreatine, 2.7.3.2)

PHYSIOLOGICAL

ACTIONS

OF

TAURINE

137

from a secondary energy source, by the enzyme creatine kinase (EC

may be replaced with guanidinopropionate or other guanidino compounds with no apparent ill effects (176, 707, 822). However, synthesis of creatine from guanidinoacetate consumes -80% of methyl group neogenesis ADP + phosphorylcreatine ~1 ATP + creatine (13) (295). Huxtable (295) has suggested that the use of creatine is a biochemical adaptation, “inefficiently but efThe equilibrium constant for this reaction is close to fectively cobbled together,” whereby enough methyl groups could be removed from methionine to produce unity, so the reaction is freely reversible. In muscle the concentrations of homocysteine required for transcells, adenine nucleotides are concentrated in two pools, sulfuration to cysteine. However, Huxtable is no expert one in the mitochondria and one adjacent to the myofiin this field and may well be wrong. brils. The reverse reaction (Eq. 13) proceeds in the mitoAsterubin, or dimethylguanidinoethane sulfonate, chondria, since ATP freshly generated by oxidative is found in the starfish, Asterias. In dogs, asterubin phosphorylation replenishes the phosphorylcreatine pool. The forward reaction occurs at the myofibrils to causes an increase in the blood glucose level, whereas taurine causes a decreased glucose level and guanidinoreplace the ATP pool depleted by contraction. Creatine ethane sulfonate causes an initial increase followed by a serves as a molecular Mercury, shuttling “high energy” fall (4). phosphate groups from power house to fireplace. In invertebrates, guanidinoethane sulfonate is Creatine phosphokinase is fairly tolerant of subformed by transamidation of hypotaurine by arginine, strate. Many guanidino compounds are accepted with guanidinoethane greater or less affinity. This tolerance preserves the followed by oxidation. In mammals, sulfonate is formed directly from taurine by transamievolutionary diversity of secondary energy sources, or dation (309, 526). The physiological function of guaniphosphagens, part of which is still represented in lower phyla where various amidino derivatives of taurine are dinoethane sulfonate in mammals is unknown. It has, pharmacological tool in used. A substance tends to assume as many identities as however, become an important the study of taurine (307). Two of the normal pharmacoit has names. The compound known variously as guanilogical weapons for probing the function of an endogedinotaurine, amidinotaurine, taurocyamine, and guanidinoethane sulfonate lives its schizoid existence in the nous substance have been in short supply for taurine. Substances that would lower taurine concentrations literature and is no exception to this unfortunate rule and pharmacological antagonists to its actions have (Fig. 16). The first name is inaccurate, as the compound, been lacking. Guanidinoethane sulfonate provides a although a guanidine, is the amidino derivative of taurine. Guanidinoethane sulfonate was originally found in partial and interim solution to both these problems. It is a competitive antagonist of taurine transport in brain a marine polychaete worm, Arenicola marina (755). It synaptosomes and perfused heart, it is convulsant under was subsequently found in other marine worms, conditions where taurine is anticonvulsant, and it prosponges, and sea anemones (1554,482) and in mammaduces retinal degeneration of the same type as is seen in lian brain and other tissues (58,230,525,817). Following cats (299, 602, 637). its use by Huxtable et al. (308), it has been widely em- taurine-deficient When guanidinoethane sulfonate is given to intact ployed as a transport antagonist for taurine and as a rats, taurine concentrations are lowered in both the taurine-depleting agent (e.g., see Refs. 65, 107, 132, 332, CNS and peripheral tissues (307). The urinary excretion 387,427,444,589). In various marine organisms, guaniof [3H]taurine is much accelerated (289). In its taurinedinoethane sulfonate is a phosphagen, acting precisely lowering action, guanidinoethane sulfonate discrimianalogously to phosphorylcreatine in mammals (98,157) nates between dietary and biosynthetic taurine, depressing the contribution of the latter more than the ADP + phosphorylguanidinoethane sulfonate H ATP former. In a tissue unable to synthesize taurine and that obtains it by transport, guanidinoethane sulfonate, if it + guanidinoethane sulfonate (14) is acting purely by inhibition of transport, should not affect the proportion of taurine in that tissue that is The enzyme catalyzing the interchange is taurocyaobtained from the diet. In a tissue, such as the liver, that mine kinase (EC 2.7.3.4) (356, 742). Other guanidino can synthesize taurine, inhibition of transport should compounds phosphorylated as phosphagens include argiresult in a lower percentage of taurine being derived nine, guanidinoacetate, lombricine, opheline, guanidinfrom the diet. The findings suggest that guanidinoethoethane sulfinate (the amidino analogue of hypotauane sulfonate is having some effect on biosynthesis as rine), and thalassemine (653). Bacteria and most inverwell as inhibiting transport. Guanidinoethane sulfonate tebrates use phosphoarginine as phosphagen (653). cannot be used as a taurine-depleting agent in cats, as Marine polychaetes are virtuosos when it comes to this species efficiently metabolizes it to taurine via the phosphagens, all the known ones being present in this action of a transamidinase (309). phylum. In fact, the puzzle is why mammals use the metabolically expensive creatine when a cheaper comI. Conclusions on energy storage bjy taurine pound would appear to be equally as effective. The methyl group in creatine is apparently functionless. 1) Phosphorylated guanidino derivatives of taurine Even in mammals, a high percentage of muscle creatine serve as phosphagens in invertebrates.


138

R. J. HUXTABLE

Volume

HN,

0

H,NCHCH,S$

O,C-NHCH,CH,SO;

w

A

B

Taurine

72

&H,OH Guanidinoethane

C

sulfonate

2-Amino-3-hydroxy-1 sulfonate

-propane

0

HzNCH,CH,SOF I

0

GH,

CH, I

6~0~

h

CH3*(CH,),CO*NCH,CO*NHCH,CH,SO~

i;~,0H D N-(2,3-Dihydroxy-n-propyl)taurine

E Decanoylsarcosyltaurine

CH;CH*NH,CH,CH,SO,O I CO,H

F

N-( 1 -Carboxyethyl)taurine

R,CHCOzCHCH,CO*NH*CHCO*NHCH,CH,SOF &H

G

A,

(&H,),&,

Cerilipin

FIG. 16. Some naturally occurring structural analogues of taurine (A). B is widespread in marine invertebrates and mammals. Cis found in various green and red marine algae (159,325, 816), and D and F are found in red algae (420,815). E is surface tension-lowering substance in alimentary canal of crab Cancer pagerus. G, taurine- and ornithine-containing lipid, is found in cell wall of bacterium Gluconobacter cerinus (746).

Z) Guanidino derivatives of taurine can pharmacologically replace creatine as a substrate for creatine phosphokinase. D. Metabolism and Energy Production

Mammals are unable to oxidize the sulfur in taurine or to cleave the C-S bond or to recycle the carbon of taurine into the general metabolic pool. To complete the natural sulfur cycle and to prevent the biological carbon pool from slowly accumulating in taurine, the metabolic abilities of bacteria are utilized. In soil samples, 50% of taurine is oxidized to sulfate within 1 wk (189; quoted in Ref. 728). Taurine is metabolized by mycelia of Aspergillus niger, supposedly to isethionate (71). Certain Streptomyces and Pseudomonas can utilize taurine as the sole source of energy, nitrogen, sulfur, and carbon (209,728), as can an unidentified bacterium isolated from sewage (378). Agrobacterium grown on taurine decomposes it to ammonia -and sulfate (320). There is considerable older literature on the use of taurine as a sulfur source for microorganisms, which may be accessed through the paper of Stapley and Starkey (728). Staphylococcus aureus is unable to cleave the C-S bond and hence cannot use taurine as a sulfur source (209). Fungi are able to use taurine as sole sulfur source, although not as sole carbon source. Bacterial overgrowth in humans and rats can lead to a loss of availability of dietary taurine. In patients

with aerobic/anaerobic bacterial overgrowth, plasma taurine concentrations are reported to fall from 153 to 80 PM (706). These values indicate, however, that a degree of cell lysis has occurred in the course of sample preparation, as true plasma concentrations of taurine in humans average -45 PM (24, 789). In both rats with experimentally induced bacterial overgrowth and in humans, electroretinogram and pigment epithelium abnormalities were noted (706). Although taurine does not serve an osmoregulatory function in bacteria (513), taurine can be detected in various species. Thus taurine concentrations in Bacillus subtiZis increase during growth and fall during sporulation (536). It appears that taurine is obtained by transport from the medium. All Staphylococcus species examined have an Na+- and energy-dependent transport system for taurine (57, 209, 717). In S. aureus, the K, for transport is 42 PM (57). Sodium-independent transport occurs in Pseudomonas aeruginosa (209). The major route of taurine metabolism involves transamination as the initial step. This yields the unstable sulfoacetaldehyde, which decomposes to acetaldehyde and sulfate (71, 378, 685, 710, 711). Two transaminases have been characterized to date: a taurine:cwketoglutarate transaminase (EC 2.6.1.55) (Eq. 15) and a taurine: pyruvate transaminase (Eq. 16) taurine

+ 2-oxoglutarate

e

HO&S. CH,CHO

+ glutamate

(15)


January 1992

taurine

+ CH,

PHYSIOLOGICAL

l

ACTIONS

CO COzH ~1 l

CH,CHO

+ alanine

(16)

Taurine:cu-ketoglutarate transaminase is found in numerous bacteria (765) and has been obtained in a stable crystalline form from Achrmobacter super&& alis (764,835). It has a molecular weight of -156,000 and is activated by pyridoxal phosphate. The reaction is reversible (767). cr-Ketoglutarate is the sole acceptor for amino transfer, but a number of donors are accepted by the enzyme. The relative activities and Michaelis constants of various substrates are, respectively, hypotaurine, 601,16 mM; ,&aminoisobutyrate, 20811 mM; ,&alanine, 184, 17 mM; and taurine, 100, 12 mM (765, 835). With hypotaurine, the reaction products are glutamate, acetaldehyde, and sulfite (750). Taurine:pyruvate transaminase (Eq. 16) has been isolated from Pseudomonas aeruginosa (709, 766). The sulfoacetaldehyde resulting from the action of these transaminases is further metabolized to acetate and sulfite by a sulfolyase (710). Sulfolyase activity is induced by taurine but is unaffected by sulfoacetate, acetate, glyoxalate, P-alanine, alanine, cysteine, or pyruvate. Mutants lacking the enzyme are unable to grow on taurine. Two paths are available for the further metabolism of acetate, one assumed and the other demonstrated. Entry into the tricarboxylic acid cycle will generate energy. Entry into the glyoxalate cycle can be used both to generate energy and to make carbon available for anaplerotic reactions (481, 711). Mutants lacking malate synthase, an enzyme in the glyoxalate cycle, are unable to grow on taurine (711). The other product of the sulfolyase, sulfite, can be oxidized to sulfate directly via sulfite oxidase (EC 1.8.3.1) or, potentially, via the two enzymes adenylylsulfate reductase (EC 1.8.99.2) and sulfate adenylyltransferase (EC 2.7.7.4) (292). This is an ATP-generating pathway that utilizes the free energy of oxidation of sulfite to sulfate. Whether it exists in microorganisms deriving their energy from the catabolism of taurine has not been demonstrated. Another route of taurine metabolism in bacteria involves the enzyme taurine dehydrogenase (EC 1.4.99.2). The enzyme catalyzes the reduction of an acceptor by taurine with the production of sulfoacetaldehyde and ammonia. The enzyme is selective for taurine, hypotaurine only being slowly oxidized (379, 380). The K, for taurine is 20 mM. The natural acceptor is unknown. I. Conclusion on taurine as energy source

Mammals are unable to oxidize taurine. Bacteria can utilize taurine as a source of energy, sulfur, nitrogen, and carbon. The first step is transamination, yielding sulfoacetaldehyde or oxidation to ammonia and sulfoacetaldehyde.

139

TAURINE

E. Surfactant

l

HO,S

OF

and Detergent Actions

Yellow bile and black bile were two of the four humors thought until comparatively recently to be responsible for the health and disposition of a person. There are numerous linguistic remnants of this outmoded concept. A melancholic person suffers from an excess of black bile. Bile is stored in the gall bladder, and we find an outpouring of bile galling if directed at us. Bile acids are detergents that serve to solubilize or emulsify fats to make them more accessible for digestion. With an insufficiency of bile, undigested fats are passed in the feces, an unpleasant condition known as steatorrhea (250). Normally, emulsified long-chain triglycerides are digested to Z-monoglycerides by pancreatic lipase. In a sense, our forebears were correct; only the language has altered. However, whether considered as a humor or a secretion, a proper flow of bile is required for good health. Bile salts are detergents because they contain both lipophilic and hydrophilic regions, the latter being hydroxy, sulfate, sulfonate, or carboxylate. Bile salts are derivatives of cholesterol. Their characteristics include free solubility in water, surface activity (lowering of surface tension), and micelle formation. In all vertebrates except for mammals, taurine is the sole amino acid conjugated with cholesterol derivatives to form bile salts (Table 5). Taurine conjugates are quantitatively the major metabolites of taurine formed in vertebrates. Indeed, for a considerable period, their formation was considered “the” physiological function of taurine. Mammals use glycine in addition to taurine. All vertebrates have bile (242-244, 262). Invertebrates have neither bile nor a true liver. Arthropods, in addition, are unable to synthesize sterols. However, the alimentary canal contains surface tension-lowering substances that serve a similar function to bile. Thus the crab, Cancer pagerus, secretes decanoylsarcosyltaurine (Fig. 16). The teleologically oldest organisms use sulfate conjugates of sterols as digestants, with this evolving in higher organisms to the more efficient taurine conjugates of steroid acids (Table 5). The insolubility of certain sulfate salts is presumably a disadvantage attendent on the use of sulfates. In other ways, also, evolution has improved the efficiency of fat digestion. The bile acids of the lower vertebrates are sulfonated in the steroid side chain rather than the nucleus, for example. The hagfish, perhaps the most primitive of the vertebrates, secretes large quantities of a poor amphiphile, myxinol disulfate. The other group of primitive fishes, the lampreys, secrete in the larval stage a rather more efficient amphiphile, Sa-petromyzonol sulfate. The gall bladder is not present in the adult form. The cartilagenous fishes, the holocephalans and selachians (sharks), also use sulfates, as do the most primitive of the bony fishes, the coelacanths. Latimeria, also a primitive bony fish, produces latimerol sulfate, a bile salt sulfated in the side chain. Higher fishes produce taurocholate. Amphibians ambidextrously use both sulfate and


R. J. HUXTABLE

140

TABLE 5. Phylogenetic distribution of conjugating acid in bile salts Family

Primitive fishes Fish

Amphibians Reptiles Birds Mammals

Primates

Species

Hagfish, shark, skate, lungfish, coelacanth (Latimeria), sucker Sturgeon, carp goldfish Catfish, herring, anchovy, pike, salmon, eel, conger, cod, mackerel, swordfish, mullet, turbot, plaice Xenopus, toad, frog, newt Some frogs, salamanders Koala, kangaroo, anteater, ground squirrel, dog, wolf, some bears, coatimundi, mustelids, mongoose, cat, sea lion, walrus, ardvaark, kudu, racoon Hare, hamster, rat fin whale, some bears, seal, pig, hippopotamus, ox, oribi, gazelle, goat, sheep Rabbit, Proechimys, fox, polar bear, sloth bear Macaca irus, capuchin Macaca maurus, baboon, orangutan, human, langur,

Conjugate

Sulfate Taurine, sulfate Taurine

Glycine Taurine Taurine, glycine

Rhesus

Data summarized

+ CoA SH + ATP + l

RCO . S CoA + AMP + pyrophosphate l

RCO Se CoA + H,NCH,CH,SOi l

R R CO NHCH,CH,SO, l

Taurine, glycine

from Refs. 243, 244.

taurine conjugates. Reptiles use taurine conjugates of Cu and Cn steroid acids, such as allocholic and coprostanic acids. These are primitive bile steroids. Birds are exclusive taurine conjugators, using the same bile steroids as do mammals. In mammals, sulfated bile salts represent the offspring of a relict biochemical pathway that still has significance under pathological conditions (204). Under normal conditions, however, the most common bile salts are either tau rocholate or glycocholate, the latter being found only in placental mammals. Tau rocholate is the more efficient bile salt, as the acidity of the sulfonate function means it remains ionized even under the highly acid conditions that may episodically occur in the upper intestine (263). Ionization is necessary for detergent action, and it also prevents precipitation and lowers absorption, thereby maintaining high intraluminal concentrations. Carnivores tend to be exclusive taurine conjugators of cholic acid (Table 5). Herbivores and omnivores tend to be both taurine and glycine conjugators and to conjugate with both mono- and dihydroxy steroids. Among the primates, New World monkeys such as Cehs conjugate only taurine, even under conditions of taurine depletion (730). Old World monkeys such as cynomolgus (Macaca), on the other hand, conjugate both glycine and taurine. If the latter is depleted, the conjugation of glycine increases (249).

72

About 24 C, steroids are known that conjugate with glycine and taurine (533). The major bile acids of humans are cholic and chenodeoxycholic acids. These are synthesized within the liver. Hydroxylation of cholesterol at position 7 is the rate-limiting step in biosynthesis. In the final two steps, the coenzyme A ester of cholic acid is first formed (Eq. lr), thereby activating the sterol for reaction with taurine (533) RCO,H

Sulfate Taurine, sulfate Taurine. Taurine Taurine

Volume

l

l

+ + CoA . SH

Bacterial action in the gut converts these primary bile salts to deoxycholic acid and a trace of lithocholic acid. Conjugation to form taurocholate is a major sink for taurine. There is a progressive dependence on dietary taurine in the series: guinea pigs, rats, Old World monkeys, New World monkeys, humans, and cats. Guinea pigs are a herbivore and thus have a taurinefree diet. They synthesize considerable quantities of taurine, excreting it in the urine (309). For bile salt formation, guinea pigs conjugate glycine only (363, 727, 787). Rats use taurine for conjugation but have a high synthetic capacity for it. Monkeys are poor synthesizers of taurine. Old World monkeys, however, can conserve taurine by switching bile salt synthesis toward glycine conjugates. Humans have very poor capacity for taurine synthesis but can also switch to glycine conjugates to conserve. Cats are unable to make sufficient taurine for their needs but must use it for conjugation (639). Thus under conditions of dietary deprivation, even after large falls in total body taurine, the absolute amount of taurine conjugated in depleted cats is the same (although the turnover of bile taurine is reduced, conserving it somewhat). Surprisingly, although no conjugation of glycine occurs in taurine-depleted cats, the isolated Ncholoyltransferase (EC X3.1.65) readily accepts glycine as a substrate (787). Humans normally produce tauro- and glycocholate in an -3:l ratio, although this varies widely from individual to individual. The ratio is a function of the availability of taurine, with increases or decreases in this producing corresponding changes in the conjugation ratio (208, 251, 771). The administration of taurine (40 pmol . kg-‘. day-l) to infants without taurine in the diet for 8 days dropped the glycine-to-taurine ratio from 3.0 to 2.2 (208). Glycine is without effect on the ratio. The anion-exchange resin, cholestyramine, lowers this ratio by binding bile salts and preventing their resorption. Both cholesterol and taurine are thereby drained from the body. The human fetus and neonate are exclusive taurine conjugators, glycine conjugation being seen after ~3 wk of life. Infants deprived of dietary taurine switch to glycine conjugation sooner (73).


January

19%

PHYSIOLOGICAL

I. Conclusions on taurine

ACTIONS

as surfactant

1) In all vertebrates except for mammals, taurine is the sole amino acid conjugated to form bile salts. 2) Among the mammals, carnivores tend to be sole conjugators of taurine, whereas other species tend to conjugate both taurine and glycine.

F. Xenobiotic

Conjugation

Taurine conjugates with various xenobiotics, the degree of conjugation varying markedly with the species (347,352). Thus in dogfish sharks, 90% of a dose of phenylacetic acid is conjugated compared with 1% in rats (342). A taurine conjugate of phenoxybenzoate is formed in mice but not in rats (281). A survey of the latter compound revealed wide differences between 25 species in taurine conjugation, ranging from 0% in vampire bats to 30% in ferrets (343). Some species, such as sheep, cats, and gerbils, only form conjugates of 3phenoxybenzoic acid with glycine; mice only form conjugates with taurine, whereas ferrets form conjugates with both acids (278). The carnivorous species, dogs, cats, and ferrets, conjugate the antihypercholesterolemic agent, clofibric acid, with taurine, but rats, guinea pigs, rabbits, and humans do not (81, 155). Dogs also conjugate 2-(2,4-dichlorophenoxy)phenylacetate with taurine. Numerous cases of the ability of taurine to conjugate with a wide variety of chemical structures are now known. Examples include the prostaglandin E, analogue trimoprostil (377), 2naphthylacetic acid (155, 256), alltrans.retinoic acid (716), and the anti-inflammatory agent, pirprofen, a 2-phenylpropionate derivative (152). Other propionate derivatives also conjugate with taurine (84). Again, there are marked species differences. Thus only rats and mice conjugate taurine with pirprofen, but only in rats is it the sole conjugate formed. Chlorinated compounds, like the important herbicida1 phenoxyacetate and phenylacetate derivatives, are also conjugated by species such as spiny lobsters (341). Unusual, however, is the observation in this case that conjugation does not hasten excretion. 2-(4-Chlorophenyl)thiazol-4-yl acetic acid (fenclozic acid) is excreted into rat bile as the taurine conjugate in a dose-dependent manner (70). At low drug concentrations, the primary route of metabolism is hydroxylation and glucuronidation. At high drug concentrations, the taurine conjugate is the major metabolite. In effect, conjugation with taurine in this instance is a “backup” system, being switched on when other pathways of conjugation are saturated. Taurine thus joins sulfate, glucuronate, and glutathione as a conjugation substrate for xenobiotics, increasing polarity, aqueous solubility, and, in most cases, clearance of the xenobiotic from the body. The relative importance of taurine conjugation is a function of the species, the chemical nature of the xenobiotic, and the dose of the drug administered.

OF

141

TAURINE

1. Conclusion

on taurine

and xenobiotic

metabolism

Numerous xenobiotics in a variety of species are metabolized in part by conjugation with taurine. G. Isethionic

Acid and Anion Balance

In marine arthropods, isethionic acid (2-hydroxyethane sulfonic acid) is the major axonal anion, with concentrations approaching 220 pmol/ml in squid giant axons (374). Despite these impressive concentrations, there have been surprisingly few investigations of the biochemistry of this intriguing substance, perhaps because of analytical difficulties. A compound containing a sulfonate and an alcohol as the only functional groups does not lend itself conveniently to automated analysis. Even its biosynthesis is uncertain. Despite initial proposals, taurine does not appear to be a precursor in the squid. Studies on isethionic acid in mammals have an unhappy and confused history. At one time isethionic acid was thought to be a major taurine metabolite that was responsible for many of the actions of taurine due to the supposed calcium-chelating abilities of this acidic substance. It is now known that only a little isethionic acid occurs in mammals, with concentrations ranging between 0.01 and 0.3 pmol/g tissue (167, 337, 674). It may, however, have as yet to be discovered functions. Is isethionic acid formed from taurine? Brain slices were reported to convert [?]taurine to [35S]isethionic acid (608), and intraperitoneal injections of tracer amounts of [14C]taurine to intact rats were shown to give rise to small quantities of isethionic acid in all tissues examined. Five days after injection, for example, 2% of the total radioactivity in the brain was in the form of isethionic acid (282). Urquhart et al. (776) found a radioactive substance in the brain eluting off an amino acid analyzer in the same position as isethionic acid after parenteral administration of [?S]taurine to rats and monkeys. However, the kinetics of elimination of isethionic acid from the brain are quite different from the kinetics of elimination of taurine, suggesting that in quantitative terms most of the taurine leaving the brain is not converted to isethionic acid first (470). The conversion of taurine via sulfoacetaldehyde to isethionic acid has been well established in bacteria. Fellman et al. (167) have been unable to demonstrate conversion of taurine to isethionic acid in homogenates and slices of heart, brain, and liver. Further investigations on isethionic acid in mammals are needed. However, the current state of knowledge can be summarized as follows. Isethionic acid occurs in rather small amounts in brain. It may or may not be formed from taurine, but if so this is not a quantitatively important route for the metabolism of taurine. Other routes by which isethionic acid may be formed not involving the intermediacy of taurine have been proposed and partially studied (162,670). Finally, the physi-


142

R. J. HUXTABLE

ological actions of taurine are not predicated version to isethionic acid. H. Taurine-Containing

on its con-

Peptides

Various taurine-containing peptides have been isolated from the brain. The percentage of the total taurine in the brain that the peptides comprise is minute. However, they may be functionally important. The first peptides were reported by Reichelt and co-workers (645, 646). One of particular interest is yglutamyltaurine or litoralon (169). This is the predominant taurine-containing peptide in synaptosomes (425, 495,783). The dipeptide is a combination of an excitatory (glutamate) and an inhibitory (taurine) amino acid. It is produced by the parathyroid gland, and it stimulates growth of thymus cultures (172, 174, 175). Numerous other hormonal actions have been claimed for it (170, 171,173). Its positive inotropic effect in the locust heart was stronger than that of taurine (171). y-Glutamyltaurine inhibits the K+-evoked release of GABA from cortical slices of mouse brain (782). The synthetic stereoisomer y-D-glutamyltaurine is a potent antagonist of the quisqualate and kainate subtypes of the excitatory a.mino acid receptor and has been used in their characterization (161). Various acylated peptides have also been reported, such as N-acetylaspartylglutamyltaurine, N-acetylaspartyltaurine, and N-acetylglutamyltaurine (496). The study of taurine-containing peptides is still in the early stages. This is an area of future growth and future discoveries. I. Other Taurine

Metabolites

Taurine is incorporated into cell surface polymers in a variety of bacteria (360,454,455,547,548). In encapsulated strains of Staphylococcus aureus, taurine is incorporated into lipids and polysaccharides where it may be involved in conferring resistance to phagocytosis (717). Typically, staphylococci live in warm-blooded animals where they are exposed to taurine. Incorporation into polysaccharides produces a negatively charged capsule surface. Antigenic polysaccharides consist of taurine, D-fucosamine, and D-aminogalacturonate from which taurine can be released by mild hydrolysis (455). In Gluconobacter cerinus, a taurine residue is incorporated into a lipid, cerilipin (746; Fig. 16). The function of the lipid is not established, and it is unknown if taurine is directly incorporated. Derivatives of both taurine and GABA, possibly the amides, are abundant in the webs of orb-weaving spiders (Argiopes and Araneus species) (23). The webs of these spiders consist of nonadhesive radial strands and an adhesive spiral. It is the latter that entraps prey. The taurine derivative is located only in the spiral, suggesting some function in disrupting prey behavior. A useful list has been prepared of the occurrence of

Vdume

72

taurine and its derivatives in marine invertebrates (15). Mono-, di-, and trimethyltaurine (the latter also being known as taurobetaine) are found in sponges. Other compounds are listed on Table 6. Marine algae contain other taurine derivatives, including D-CySteindiC acid (2-amino-3-hydroxy-l-propane sulfonic acid) (159, 325), N-carboxyethyltaurine (420), and N-(2,3-dihydroxy-n-propyl)taurine (815, 816) (Fig. 16). VII.

CONCLUSIONS

From the myriad studies on taurine, does any pattern emerge to organize the disparate mass of information available? Perhaps some cautious conclusions can be drawn. The most pervasive action of taurine, an action that is independent of molecular structure, is that of an osmolyte. Any soluble compound has the same property. The osmotic action of a compound is a direct function of its molar concentration; it is a colligative action. In considering such an action, one is discussing physical chemistry and is not yet in the realm of biology. Consideration of the osmoregulatory action of a compound, however, brings us into biology, where now molecular structure becomes important. Taurine has specific chemical and biochemical attributes that are of advantage to an osmoregulatory substance: its inertness, relative ionic neutrality at physiological pH, lack of metabolic function in most cells, poor diffusibility across cell membranes, and relatively high solubility. Osmoregulation is not an action unique to taurine. In bacteria and certain marine invertebrates, taurine appears to be of secondary importance to other amino acids. In other marine organisms, taurine is primus inter pares: quantitatively the most significant substance but sharing the overall responsibility for the osmoregulatory adaptation of the cell with a range of other substances. In higher organisms, alterations in the concentrations of inorganic ions become important. In such organisms, for a properly modulated response to an osmotic stress, a mechanism is needed to link the changes in inorganic ions with the changes in low-molecular-weight osmolytes. This is achieved in a number of ways. The Na+ dependency of amino acid transport, the linkage of ion and amino acid movements via Na+K’-ATPase, the dependence of active transport on ATP availability, the alterations in membrane permeability consequential on altered Ca2+ concentrations, and other mechanisms all link amino acid movements and the movements of inorganic ions. Inorganic ions, however, can have profound effects on cells that are unrelated to their osmotic actions. These include alterations in membrane potential and electrical activity, enzyme activities, chelation of adenosine nucleotides, conformation of cell macromolecules, including nucleic acids, and an untold host of other effects. The admittance of ions into a cell, therefore, has to be handled as cautiously as Greeks bearing gifts. In view of the interrelationships between ion and amino acid movements, it is natural that modulation of


PHYSIOLOGICAL

ACTIONS

143

OF TAURINE

January

1992

TABLE

6. Distribution of taurine and its derivatives in marine invertebrates Phylum Compound

Porifera

Hypotaurine Taurine Guanidinoethane Guanidinoethane N-methyltaurine Dimethyltaurine Trimethyltaurine Isethionic acid

+ +

+ +

+ + + +

+

sulfinate sulfonate

* Also designated Cnidaria.

Coelenterata*

Sipuncula

Mullusca

Annelida

+ +

+ + + +

+ +

Crustaceat

+ +

t Crustacea is a class in the phylum Arthropoda.

ion entry by taurine evolved. The passage of both ions and amino acids into and out of the cell is controlled by the membrane. This is an obvious point at which taurine evolved to modulate Ca2’ entry. Osmoregulation means giving the cell the capacity for osmotic adaptation: in other words, allowing the cell to respond to the stress of a changing environment. In many of the other functions taurine has assumed, this is the common thread, a permissive effect on the ability of the cell to respond to an externally applied stress. In the main, pharmacological effects of taurine are observed only in stressed systems, whether it be the stress of altered Ca2+ concentrations perfusing the heart, an epileptogenic stress in the central nervous system, the oxygen paradox, cell isolation or proliferation, or an osmotic stress. Similarly, changes in taurine concentrations typically occur only in stress states, including osmotic changes, anoxia, prolonged illumination of photoreceptors, or congestive heart failure. Even cell proliferation or brain development can be considered a type of internally generated stress. Can any common deductions by made about taurine and stress states? Taurine protects the cell from the disrupting effects of exterior changes transmitted into the cell via such means as alterations in inorganic ion concentrations. To that extent, taurine is a stabilizing influence in an unstable molecular world. All of the actions of taurine listed tend toward conservation of function, a property that has been termed enantiostasis (493). Enantiostasis differs from homeostasis in that the effect of a change in the chemical and physical properties of the internal milieu of a cell is opposed by a further change. Thus, although the milieu is unstable (i.e., there is no homeostasis), the functioning is stable. Changes in taurine concentrations during osmotic stress, or the other stresses discussed, can serve enantiostatic functions. Enantiostasis by taurine occurs in conjunction with other regulatory mechanisms. One of the more significant of these is provided by the cell membrane. Membranes evolved to yield a private space in which the disorganization and lack of stasis of the external world could be excluded and controlled. The lipophobic cytosol and hydrophobic lipid membrane share the common

[Data summarized

from Allen and Garrett (15).]

function despite opposing chemistries of maintaining an appropriately hospitable environment for proteins to function in. Taurine provides a molecular link between these two phases. Cells with rigid walls do not experience the same pressures to adapt their intracellular milieus to the extracellular environment. An insulated brick house does not need the flaps, guys, fly sheets, and mosquito screens required for a sometimes comfortable existence in a tent. In multicellular organisms, the extracellular environment is in a continually changing biochemical and hormonal state, secondary to changes in the external environment. Cells, in turn, must respond to the changing conditions around them. In complex organisms, taurine is highest in cells that respond continuously to the environment. These include electrically excitable cells, such as photoreceptors, neurons and myocytes, and secretory structures. Taurine antagonizes the tendency to change produced by a changing environment; it is a membrane stabilizer, concentrations tend to increase under stress, and the whole cellular tendency of taurine is toward enantiostasis. Life is lived at the interface between organization and chaos, between the ordered crystal and the random fire. The process of evolution as much as the life of an individual is a constant restructuring that delays the intrusion of chaos with the resulting dark night of extinction of life or of a life. Taurine, perhaps, is one of those protean molecules, along with water and the inorganic salts, helping to produce an orderly cellular response to the continuous random changes around the cell. Such a response tends to conserve function and delay the inevitable dissolution of such an inherently unstable entity. Edward Gibbon, author of The Decline and FaZZ of the Roman Empire, wrote, “Let no man who builds a house or writes a book presume to say when he shall have finished. When he imagines that he is drawing near to his journey’s end, Alps rise on Alps, and he continually finds something to add and something to correct.” If this sentiment holds for the study of history, it certainly holds for a rapidly evolving field of scientific study. Incomplete as it is, however, perfection in a re-


144

R. J. HUXTABLE

view is not to be achieved. If this review is useful to those working on taurine or stimulates them or others to investigate further the interesting biology of this simple but profound substance, it will have fulfilled its purpose, despite its imperfections. I thank Anders Lehmann, Barry Lombardini, Simo Oja, Pirjo Saraansari, Arne Schousboe, and John Sturman for their detailed, critical, and helpful comments on this review. REFERENCES 1. ABE, M., K. SHIBATA, T. MATSUDA, AND T. FURUKAWA. Inhibition of hypertension and salt intake by oral taurine treatment in hypertensive rats. Hypertension DaZZas 10: 383-389,1988. 2. ABE, M., M. TAKAHASHI, K. TAKEUSHI, AND M. FUKUDA. Studies on the significance of taurine on radiation injury. Radiat. Res. 33: 563-573, 1968. 3. ABE, M., T. TOKUNAGA, K. YAMADA, AND T. FURUKAWA. y-Aminobutyric acid and taurine antagonize the central effects of angiotensin II and renin on the intake of water and salt, and on blood pressure in rats. Neuropharmacology 27: 309-318,1988. 4. ACKERMANN, D., AND H. A. HEINSEN. Uber die physiologische Wirkung des Asterubins und anderer zum Teil neu dargestellter, schwefelhaltiger Guanidinderivative. 2. Physiol. Chem. 235: 115-121,1935. 5. AGNISH, N. D., G. RUSIN, AND B. DINARDO. Taurine failed to protect against the embryotoxic effects of isotretinoin in the rat. Fundam. Appl. ToxicoZ. 15: 249-257,199O. 6. AGRAWAL, H. C., A. N. DAVISON, AND L. K. KACZMAREK. Subcellular distribution of taurine and cysteinesulphinate decarboxylase in developing rat brain. Biochem. J. 122: 759-763,197l. 7. AGRAWAL, H. C., AND W. A. HIMWICH. Amino acids, proteins and monoamines of developing brain. In: DevelopmentaL Neurobiology, edited by W. A. Himwich. Springfield, IL: Thomas, 1970, p. 287-310. 8. AGUILA, M. C., AND S. M. MCCANN. Stimulation of somatostatin release from median eminence tissue incubated in vitro by taurine and related amino acids. Endocrinology 116: 1158-1162, 1985. 9. AKERA, T., D. KU, AND T. M. BRODY. Alterations of ion movements as a mechanism of drug-induced arrhythmias and inotropit responses. In: Taurine, edited by R. J. Huxtable and A. Barbeau. New York: Raven, 1976, p. 121-134. 10. AL-BEKAIRI, A. M., H. A. EL-SAWAF, AND A. R. ABUJAYYAB. Effects of bromocriptine and taurine on avoidance learning performance in the rat. Med. Sci. Res. 17: 393-394,1989. 11. ALBERTS, A., AND E. P. SERJEANT. Ionization Constants of Acids and Bases: A Laboratory Manual. London: Metheun, 1962. 12. ALDEGUNDE, M., I. MIQUEZ, I. MARTIN, AND M. P. FERNANDEZ OTERO. Changes in brain monoamine metabolism associated with hypothermia induced by intraperitoneally administered taurine in the rat. IRCS Med. Sci. 11: 258-259,1983. 13. ALEXANDROV, A. A., AND A. S. BATUEV. Intracellular studies of GABA and taurine action of the neurons of the cat sensorimotor cortex. J. Neurosci. Res. 4: 59-64, 1979. 14. ALGER, B. E., AND R. A. NICOLL. Pharmacological evidence for two kinds of GABA receptor on rat hippocampal pyramidal cells studied in vitro. J. PhysioZ. Lond. 328: 125-141, 1982. 15. ALLEN, J. A., AND M. R. GARRETT. Taurine in marine invertebrates. Adv. Mar. BioZ. 9: 205-253, 1971. 16. ALLEN, J. A., AND M. R. GARRETT. Studies on taurine in the euryhaline bivalve Mya arenara. Comp. Biochem. PhysioZ. A Comp. Physiol. 41: 307-317, 1972. 17. ALVAREZ, J. G., M. K. HOLLAND, AND B. T. STOREY. Spontaneous lipid peroxidation in rabbit spermatozoa: a useful model for the reaction of O2 metabolites with single cells. In: Oxygen Transport to Tissue-V, edited by D. W. Lubbers, H. Acker, T. K. Goldstick, and E. Leniger-Follert. New York: Plenum, 1983, p. 433-443.

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Compounds:

Novel

Biochemical

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Structure and physiological actions of ghrelin.

Physiological role of taurine--from organism to organelle.

Comparison of the central nervous system actions of taurine and N-pivaloyltaurine [proceedings].

Social interactions affecting caste development through physiological actions in termites.

Comparative Physiological and Transcriptomic Analyses Reveal the Actions of Melatonin in the Delay of Postharvest Physiological Deterioration of Cassava.

Inhibitory postsynaptic actions of taurine, GABA and other amino acids on motoneurons of the isolated frog spinal cord.

Anti-Fibrotic and Hepatoprotective Actions of Taurine and Silymarin against CCl4 Induced Rat Liver Damage.

Non-linear actions of physiological agents: Finite disarrangements elicit fitness benefits.

Polarized binding of lipoprotein lipase to endothelial cells. Implications for its physiological actions.

CTGF and its role under physiological and pathological conditions.

Actions of Prolactin in the Brain: From Physiological Adaptations to Stress and Neurogenesis to Psychopathology.

The neuropharmacology of taurine.

Taurine: retinal function.

Taurine abated subacute dichlorvos toxicity.

Tissue taurine content, activity of taurine synthesis enzymes and conjugated bile acid composition of taurine-deprived and taurine-supplemented rhesus monkey infants at 6 and 12 mo of age.

Beneficial effect of intravenous taurine infusion on electroretinographic disorder in taurine deficient rats.

Effect of taurine on wound healing.

Mechanism and regulation of peroxidase-catalyzed nitric oxide consumption in physiological fluids: critical protective actions of ascorbate and thiocyanate.

Taurine flux in chicken erythrocytes.

Fundamental studies on physiological and pharmacological actions of L-ascorbate 2-sulfate. I. On the hypolipidemic effects.

Antibodies to neuropeptides as alternatives for peptide receptor antagonists in studies on the physiological actions of neuropeptides.

Molecular actions of two synthetic brassinosteroids, iso-carbaBL and 6-deoxoBL, which cause altered physiological activities between Arabidopsis and rice.

Neuroprotective Mechanisms of Taurine against Ischemic Stroke.

Effect of taurine in chronic alcoholic patients.