BILE SALT SECRETION E. R. L, O'M~ille

Department of Physiology, University of Liverpool, Liverpoo! L69 9BX. IT is well established that bile formation ! does not occur simply by hydrostatic ultrafiltration from the blood but requires the action of several secretory processes, one of which is the secretion of bile salts. It is impossible to understand the role of the bile salts in the formation of bile without some knowledge of their physicochemical properties. The commonest bile salts are conjugates of cholie acid. Chelic acid, which is synthesized in the liver from cholesterol, is the C~ steroid, 3 ~, 7 e, 12 e -trihydroxy- 5 ~-cholanoic acid (R.C=OOH). ]t is actively conjugated in the liver with glycine or taurine (a peptide link is formed), both conjugates being present in human bile; only taurine conjugated bile salts occur in dog bile, the principal one of which is taurocholate, which may be represented as R.CO.NH.CH=.CH,.SO~-. The conjugated bile salts exist almost entirely in the ionized form at the pH values which prevail in the plasma, liver cell or bile. In blood most of the bile salt is combined with plasma protein (albumin). The hydrophilie groups on the bile salt molecule (i.e. the three OH groups attached to the steroid nucleus and the -CO.NHand SO, groups on the mobile side chain which taurocholate possesses) all project or are disposed on the same 'side' of the steroid nucleus; the CH~ subsftueuts at C-t0 and C-t3 and the H at C-5 all project on the other, hydrophobic side. The bile salts are therefore classed as 'amphipaths' or 'amphiphiles' (sympathy for or loving both water and oil). The principal bile salts are highly soluble in water. Above a certain critical temperature and concentration (beth normally exceeded in bile) the hydro-

phobic sides of the bile salts spontaneously interact to form molecular aggregates (micelles); if lecithin and cholesterol, which are insoluble amphipaths, are also present, as in bile, they are solubilized by forming mixed micelles with the bile salts. The interacting hydrophobic parts of the amphipaths lie in the interior of the micelle, while their hydrophilic groups project on the outer aspect and interact with the surrounding water molecules. In vitro, in a single taurochelate-lecithin micel[e, saturated with lecithin, there may be 62 molecules of bile salt and 125 molecules of lecithin. The above physiochemical properties are described authoritatively by Small (t971), Carey and SmaJJ (1972), and Hofmann (1976). Certain important consequences which bear on bile formation follow from these properties of the bigary amphipaths. (i) Since lecithin and cholesterol are poorly soluble in water it fel~cws that the substantiaJ biliary transfer of these substances which takes prace must be almost entirely dependent on bile salt secretion; it has been found that the excretion of lecithin and cholesterol into bile increases in hyperbolic fashion with increasing bile salt secretion rate (Wheeler and King, 1972; Wagner et al., 1976). (ii) Sometimes, particularly at very low secretion rates of bile salts (which would be most marked during fasting) bile may become So supersaturated with cholesterol that this insoluble molecule may crystallize as bile later rests in the gallbladder, thus, perhaps, initiating gallsones. (iii) The osmotic coefficient (osmolality/total solute concentration) of bile is greatly reduced by micelte formation and its associated binding of

BILE SALT SECRETION counterions, thus ~owedng the net potential for 1he osmotic entry of fluid into the biliary tract. (iv) In relation to bile salt transfer the effective bile salt concentration in bile is probably just that which surrounds and is in equilibrium with the mixed micelles and therefore only a very small fraction of the total concentration, The secretion of bile salt by the liver is thought to be an active process for the following reasons (i) The effective concentration of bile salt in bike is norma~y very much greater than the effective (i.e. unbound) concentration in plasma or liver cell. Although a bile:plasma concentration ratio (the bile: liver cell ratio is uncertain) of 250~00 is readily attained it cannot be stated with certainty that the transfer of the bile salt anion into bile is against an eJectro. chemical gradient, since the difference in electrical potential that may exist between the blood sinusoidal face or between the inside of the liver cell and the b~Ie cana~icu~us ~s not known. However the potential required to balance the observed concentration ratio at electrochemical equilibrium (calculated from the Nernst equation, in this case 61.5 log,, 275) would need to have the improbably high value of about 150 mV (bile canaliculus positive). (ii) The secretion of bile salt reaches a maximum value in the face of an ever-rising concentration of bile salt in the blood, produced by infusing bile salt at a high rate ( W h e e l e r e t a l . , 1 9 6 0 ) . (ig) Competition between bile salts for transfer has been observed (O'M&ille et al., 1965; Glasinovic et at,, 1975a). Xransport processes which exhibit these characteristics are thought to be mediated by 'carriers' present in limited number in the cell membrane. The maxLmum rate at which taurochol. ate can be secreted is rlm[ted by transfer from within the liver cell into bile and no1 by the uptake process from the plasma (O'Maille et at., 1969). Glasinovic et ah (I975b) have shown that the uptake process 1or tauropholate is also satur-

191

able, but consistent with the previous finding its maximal rate of transfer is at least six times the biliary transport maximum we obtained in our dogs (O'M&ille et al., 1965). These saturable processes may be mediated by the bile salt specific receptors which have recently been identified in isolated hepatic surface membranes (Accatino and Simon, 1976). The disposition of bile salt within the liver cell is unknown. If the total bile salt concentration (0.14- 0.28 mM) given 1or the Fat liver cog by Greir~ and Popper (1971) were all in the unbound form it would greatly exceed the unbound concentration in plasma, and would thus require the uptake process to be active since transfer would be against an electrochemical gradient (the inside of the cell is negative with respect to the sinusoidal face). By analogy with other organic anions transferred by the liver it is more likely that bile salt is tightly bound lo hepatocytoplasmic protein; the unbound concentration within the. liver c~ll could then be less than in plasma, in which case uptake might occur by passive facilitated transfer. The (rate limiting) transfer of bile salt from within the liver cell into bile is generally assumed to be active. It is not known whether the bile salts are secreted into bile first, with lecithin and cholesterol following secondarily, or whether they are secreted already complexed wlth the other biliary amphipaths. Since dehydrocho]ate derivative (O'M&ille and Richards, 1976) and taurodehydrocholate (both non-micelleforming bile salts in the dog) interact competitively with taurocholate, it is probab[~ that even if a complex is secreted, it is likely to be the bile salt component which combines with the membrane carrier. The studies of Acatino and Simon (1976) with isolated surface membranes (see above) would also seem to confirm this. Once in bile Ihere is probably a physico-chemical equilibrium betweert the lecithin and Cholesterol in the biliary micelles and these lipids in

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the m e m b r a n e (see W h e e l e r and King, 1972 for kinetic analysis); the letter are, in turn, prebebty in d y n a m i c e q u i l i b r i u m with the intracellular peel of lecithin a n d cholesterol (Gregory ef el., 1975). It is we(l estabtished that in m a m m a l s the bite salts are all n o r m a l l y transferred into bile virtually completely c o n j u g a t e d (Hofmann, 1976) In the early sixties there was some d o u b t about whether the liver had the ability, u n d e r a n y circumstances, to secrete u n c o n j u g a t e d or free bile salt into bile; indeed in 1964, Combos, in a review article expressed the v i e w that c o n j u g a t i o n was obligatory for the secretion of bile saJts. At the very same time (reference in O'M&ille et al., 1965} it was apparent to the writer a n d cob leagues that the liver of the dog was readily capable of secreting free chelate if chelate were administered. Furthermore it was f o u n d that the hepatic store of taurine c o u l d in the space of a fairly short time be depleted by c o n t i n u o u s chelate infusion and after this, infused chelate appeared in bile largety in the u n c h a n g e d form (see Fig. 1). (The intraportal administration of taurine promptly reversed these c h a n g e s ) . This discovery e n a b l e d the secretory characteristics of free chelate to b e studied. It therefore b e c a m e possible to assess the i n f l u e n c e of c o n j u g a t i o n on lransfer of chelate by comparing with each other the secretory characteristics of (i) synthetic t a u r o c h o h ate, (it) chelate w h i c h was first actively conjugated in the liver before being secreted into bile and (/it) chelate w h i c h was transferred from blood to bile largely in the u n c h a n g e d form, after acute taurine depletion. In these experiments either constant infusions (O'M&ille et al., 1965, 1967; R i c h a r d s and O'M~ille, 1973; O'Maille and Richards, 1977) or single injections (O'M~Nle et el., 1969) of bile sa/ts were given systemically to anaesthetized dogs in w h i c h the c o m m o n bile duet was c a n n u l a t e d and the cystic d u c t tied; bile was collected in graduated tubes and blood samples taken from systemic and hepatic veins.

00,

'~ oo3 "~ ~=

o

{321~ o 105

I

p~o~dt

Time Imin) Fig. 1--The production of acute ~aurine depletion in the anaesthetized dog by chelate infusion and the differences in secretory characteristics between chelate transferred free and choJate which is first actively conjugated. Chelate was infused (C in - - -) systemically lhroughout at 3.3 /Lmele/ rain. kg body wt. At first most of the infused chelate w~s conjugated in the liver and secreted as taurocho[ate (TC out ~, ~ ). After taudne depletion most of the infused chelate was secreted free (C out X - ~ ) The intraportal admin[~ tration of taurine (begun at Ihe arrow T) promptly r~ersed these change~. The plasma concentration of tolal chorale (Plasma S---0, ~M § 2) was elevated (ie. clearance was reduced i when chelate was being ~creted mainly free compared to when being secreted mainly eo~iugated before taur[ne depletion. Or alter 1he administralion of taurine; in the Imler phase lhe output of bile salt temporarily exceeded input due to 1he Loll-loading' of chelate which had accumurated in the animal during the phaSe of taurine depletion Mainly free chelate secretion was al~o associated with a higher bile flow r~le tS,F,R A-dj~) and correspondingly lower total (conjugated plus free) chelate concentration in bile (nile ~ - 9 raM). (From O'M&il[e ~t el, 1965: J. Phyeiol /Lend.), 180, 67) The secretory characteristics used for c o m p a r i s o n w e r e : (i} the steady-state hepatic c l e a r a n c e s o1 bile salt (tater the c o m p o n e n t s of clearance, n a m e l y the extraction fraction a n d blood flow rate, were each d e t e r m i n e d ) , (it) the maxim u m rates at w h i c h the bile salts c o u l d be secreted into b i l e and (iii) the bite flow rate excited p e r mole of each bile salt secreted.

BiLE SALT SECRETION The steady-state hepatic plasma clear+ ance of infused bile salt (C, ml/min) is given by its hepalic uptake, secretion or infusion rate (since extrahepadc losses were negligible) (Q, /~mole/min) divided by its concentration in systemic plasma (F, #mole/ml). The hepatic clearances of conjugated chelate were greater than those of chelate secreted free (see Fig. 1). By definition clearance (Q/F) is a[so equal to the fraction of bile salt removed from unit volume of plasma flowing through the Iiver (the extraction fraction, E) multiplied by the volume flow rate of plasma through tee liver (P, ml/ rain); that is (if H (Fmole/ml) is the hepatic venous plasma concentration): C = Q/F = P x (F-H)/F = P x E, since Q = P x (F-H) and E -- (F-H)/F. To exclude the effects of variations in hepatic blood flow rate on clearance it is necessary to express the dillerences in fhe liver's ability to remove bile salts as differences in extraction fraction at the Same blood flow rete in all cases (O'Maille etal., 1967). In these experiments plasma flow rate was obtained by the Fick principle (P = Q/(F-H)) and the liver blood flow rate from this by multiplying by 10g/(100-haematocrit (%)). (These calculations apply accurately to taurocholate, which remains confined to the plasma but flow rates are overestimated in the case of cholete which enters red cells to some extenl (O'MEiille et af,, 1967). The hepatic exlraction fraction of synthetic taurocholate {92 • 5% (S.D.}) or of actively conjugated chelate (79 ~ 8%) was much greater than that of chelate secreted free (47 c 15%) (mean blood flow of 1.8 ml/ mln. g liver). The extraction 1faction of synthetic taurocholate was also significantly greater than that of activeLy conjugated chelate (O'M&ille and Richards, 1977). The bile salt infusion (and secretion) rate during these studies was of course submaximal (about 3/zmolejmin. kg) but was much greater than the highest that could ever be reached in the dog in the course of digestion of a meal

~93

(O'Maille and R[chards, 1977); taurochelate in the normal life of the dog must therefore be almost completely removed from the pcrtat blood in its first passage through the liver. The maximum secretory rate of bge salt was determined either by infusing bile salt at progressively increasing rates until no further increase in bile salt secretory rate took place or by administering bite salt from the beginning at a rate well above the expected maximum secrelory rate. The relation between the biIe salt secretory rates obtained during these infusions and the bile salt concentrations in plasma was hyperbolic. The maximum secretory rate of synthetic taurocholate (8.6=1.4 (S.D.) #mole/min. kg body wt.) or of actively conjugated chelate (6.9+1.3 J~mo]e/min. kg total chelate, three quarters conjugated) was much greater than that of free chelate (4.2 + 0.9 /~mole/min kg total chelate, four fifths free). The taurocholate secretory maximum was a~so significantly greater than that for actively conjugated chelate (O'M&il]e and Richards, 1977). During the administration of chelate in the presence of excess taurine, the maximum output rate of taurocholate (about 5.2 /zmole/min. kg) appeared also in some experiments to be the maximum rate at which conjugation could take place in those particular circumstances. There is clearly a very large safety margin in the liver for both the conjugation and secretion of bile salts, since the peak en{erohepadc presentation rate of taurechelate that occurs during normal digestion is probably under 2 #mole/rain. kg and that of free bile salt (arising from deconjugation in the intestine) much less still (O'M&ille and Richards, 1977). It is clear from the above experimental work that when taurine is unavailable, while the liver has the ability to secrete free chelate in large amounts, the resulting secretory performance is not as good as when cqn~ugation is possible. (The -same, incldentally, applies to the secretion of 'dehydrocholate' (O'M~ige and

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Richards, 1970)). The explanation for the inferior secretory performance of free chelate is not clear. This problem has recently been investigated (O'M&ille and Richards, 1977) but only a brief comment and some results will be given here. Since bile salt secretory rate is a net rate the lower maximum for free chelate could arise from a lower unidirectional transfer rate into bile (mainly active from the liver cell) or a greafer unidirectional transfer rate out from the biliary tract (back-diffusion) or both. The passive efflux of bile salt from the bile to the liver cell or blood is given by the product of {he (passive) permeabilitly coefficient (ease with which solute passes through a membrane) and the effective concentration of bile salt in bile. In our experiments beck diffusion of un-ionized cholie acid (only 1 per cent of the total is present in this form at the observed bfliary b H of 7.5) was not important. Back diffiusion of ionic chelate, while believed to be greater than that of Inurechelate, was also considered to be quantitatively unimportant. So the lower free chelate secretory maximum was thought to be due to a lower undirectionaf transfer from the liver cells either through different chelate-membrane carrier kinetics (although this does not appear to apply in the rat liver (Paumgarfner et al., 1973) ) or due to the inhibitory effects of a raised concentration of an intermediate in the conjugation pathway, cholyl CoA. This substance normally reacts with taurine to form taurocholate; following taurine depletion this reaction is impossible, so, it is postulated, cholyl CoA would accumutate and inhibit free chelate secretion either competitively or due to deprivation of CoA. The administration of taurine, which promptly improves secretory performance, would reduce the concentration of cholyl CoA (due to its rapid conversion 1o taurochelate) and increase that of CoA. Except where otherwise indicated the statements made in this paraqraph are based on a study by O'Mi&ille et al.

(1969). Following single intravenous injection, bile salts leave the plasma very rapidly (Josephson, 1941), the plasma bile sag concentrabon in our experiments having fallen after about 3 rnin to half its initial value if that is considered as dose/plasma volume. Apart from the first few minutes after injection the concentration of taurocholate in plasma declines more rapidly than that of chelate. The secretion of bile salt into bile is much slower than the rate at which it leaves the plasma (see below) so the liver content of bile salt must rise steeply in the early phase after injection. Taurochelate is also efirninated in the bile more rapidly than both chelate which is mostly conjugated in the liver en route to bile and chelate which is secreted largely free after acute taurine depletion. At a dose of 0.12 m-mole/kg the time taken for the first 50 per cent of its bJiiary secretion was 12.7 + 1.18 (S.D,) min for taurocholate and 18.9-1.8 min for chelate (in taudne replete dogs). Recently Hofmann and colleagues (Cowen et a[., 1975) have studied the elimination from plasma o1 single injections of radioactively-labelled bile salts in humans; as in dogs, taurocholate was eliminated more rapidly than chelate. (In relation to clinical work it is of interest to mention that Hofmann and colleagues (Korman et al., 1975; Las Russo et at, 1975) have found the elimination rate of a single small injection of glycocholate (measured in plasma by radioimmunoassay) to be a more sensitive detector of liver injury than conventional tests of fiver function (the compartmental brornsulphthalein test (Richards, 1965; Short, 1969) was not included in the comparison) ). It has been known for a long time thai the increase in bile flow rate that follows the administration of bile salts is associated with the ,secretion into bile of the admrnistered bile salts themselves, Sperber (1959) suggested that this increase in flow may follow osmotically the active secretion of bile salts into the

BILE SALT SECRETION bile canalicu[us (a narrow (1 i~m diameter) channel into which rnicrovilli protrude, that provides the ideal structural basis for local osmosis (Diamond and Tormey, 1986)). Thus the sequence might be: first the transfer o1 the bile salt anion and its counterion (chiefly Na I ) into bile, then water (solvent) llow along an osmotic gradient with dissolved constituents in plasma or liver cell (e.g. other electrolytes) being dragged along, their final concentration in bile being determined by the extent to which they were 'reflected' or restricted by the epithelial barrier and by the requirements of electrochemical equilibrium. The osmolality of bile is approximately the same as that of plasma. A linear reIation between bite saff secretion rate and bile flow rate has been demonstrated in all ef the many species which have been studied (Wheeler, 1972). Chloride and bicarbonate transfer rate are also linearly related to bile salt secretion rate, In accordance with osmotic theory the increase in bile flow rate per unit increase in the secretion of a nonmiceile-forming bile salt like 'dehydrochelate' is much greater than that for a miceHe-lorming bile salt like taurocholate (O'Maille and Richards, 1976). In general, at least in experiments on acutely prepared animals, extrapolation of the straight line obtained for the relation between bile salt secretion rate and bite flow rate gives a positive intercept on the bile flow rate axis i.e. some bile flow at a bile salt secretion rate o1 nought. This 'bile salt independent flow', which is relatively very high in the rat and rabbit and low in the dog and human is probably secondary to the active pumping into the bile canaliculus of sodium followed passively by chloride (Erlinger and s 1974). However it is now being increasingly realised that this flow, while not being due to the osmotic effect of the secreted bile salt, nevertheless can be influenced by bile salts affecting the sodium p u m p which initiates it (see below).

195

One of the more striking observations made during the constant infusion of chelate at submax~ma[ rate was the pronounced increase in bile flow rate which occurred when free chelate secretion rose sharply (after taurine depletion) to become the predominant bile salt in bile (Fig. 1). For example the average total (mainly free) chelate secretion rate of 3.21 /~mole/min. kg was associated with a bile flow rate of 51.4 /d/rain. kg. Secretion of taurocholate at the same rate was associated with a bile flew rate of only 31.4 /zl/rnin.kg (O'M&ille and Richards, 1977). After recent investigation and analysis of the cause of this dramatic extra choleresis associated with free chelate secretion it was concluded Ihat it was 1argely independent of the osmotic effect of chelate secretion and had to be due therefore to some other mechanism, e.g. {he preferential stimulation by chelate of the sodium pump (O'MAille and Richards, 1977). Other observations which suggest that bile salts may stimulate the sodium pump mechanism of bile flow can be found in O'MAille and Richards (1976) More direct evidence has recently been provided by Wannagat et al. (1976) who showed that in circumstances of prolonged raised bile salt secretion by the rat liver both the 'independent flow' component and the activity of the N a K activated ATPase (an essential component of the sodium p u m p ) in isolated ' canalicular' membranes were substantially raised. It thus seems likely that {he term 'bile salt independent flow' will become an increasingly confusing one for this particular component of bile formation. Bile salt secretion can exert very marked and at first sight paradoxical effects on other organic anions concentrated in bile. When taurocholate was administered during the course of a very high bromsulphthalein (BSP) (a large, foreign organic anion concentrated in bile) infusion the initially determined BSP transport maximum was found to in-

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IRISHJOURNALOF MEDICALSCIENCE

crease almost threefold (O'M~ille et al., 1966). In seeking an explanation for this phenomenon we were at that time greatly influenced by the work of Conway (1960) and Conway et al. (1961) on what appeared to be a critical energy barrier far the secretion of sodium ions from frog skeletal muscle. Adapted to BSP secretion it was considered that the effective concentration of BSP in bile above a certain critical value might impose a barrier on the dissociation of BSP from its carrier on the biliary face of the cell. Bile salt transfer, with its associated increased canalicular flow, wou!d then enable increased transfer of BSP without this critical value being reached. This theory has been very seriously challenged by the subsequent findings that increases in canalieular bile flow produced by non-bile salt agents such as theophylline (Erlinger and Dument, 1973; Barnhart et el., 1973) and the bicyclic organic acid SC 2644 (Gibson and Forker, 1974) do not elevate the initial BSP secretory maximum. However if BSP is incorporated in rnicelles, or complexed in some other way, its effective concentration in bile need not necessarily be reduced by the hydrochforesis caused by such agents since the natural biliary micelles might well be disaggregated by dilution (Wheeler and King, 1972). Interestingly Gibson and Forker (1974) failed to produce enhancement of the BSP maximum with dehydrecholate when infusion of this non-rnicelle-forming bile salt was superimposed on a 8SP secretory maximum which itself was established during the continuous infusion of taurocholate at a very low rate. The initial BSP secretory maximum obtained in our experiments without a 'background' taurecholate infusion, was cleady enhanced by dehydrocholate administration although the effect was not nearly as powerful as that with taurocholate. Bamhart et ah (1973) obtained similar results. Whether some form of compiexing of BBP with 'dehydrocholate' itself can occur is not known.

Thus the effective concentration of BSP in bile may still be an important determinant of the 8SP secretory maximum although not necessarily by imposing a critical energy barrier on BSP dissociation from its carrier. Conventional reversible membrane carrier theory would require enhanced BSP maximal transfer to be associated with a fall in the effective BSP concentration in bile if the bile salt (a) did not have any additional effect on the diffusion coefficient of the BSP-carrier compte• within the membrane or (b) did not cause allosteric modification of the carrier itself. To summarize, bile salts r~ay enhance the BSP secretory maximum through (i) an influence on the effective concentration of BSP in bile or (it) an atlosteric modification of the BSP membrane carrier (this is favoured by Forker and Gibson (1973) or (iii) increasing the diffusion coefficient of the BSP-carrier complex in the membrane, or (iv) increasing the number of functioning carriers for BSP, for example by 'opening up' previously non-secreting parts of the liver. (The max~murn secretory rate of the unconiugated dibromsuJphthalein (DBSP) is also greatly enhanced by taurocholate administration). Taurocholate or taurocholate-choleresis enhances the b[lirubin transport maximum in the dog (Goresky and Kluger, 1959) and the transpor~ of unconiugated bilirubin in the Gunn rat (Callahan and Schmid, 1969). Recently Biss81 et el. (1975) using adult rat hepatocytes in culture, have shown that only in a bile salt rnicellar or m~xed micstlar environment are the celJs able to rid themseJves extensively of the conjugated bilirubln formed within them. In recent years the enterohepatic circulation of the bile salts s a whole, in both normal and abnormar circumstances, has been intensively investigated (Dowling, 1972; Small et al., 1972: Hofmann, 1926) but a description of its characteristics is beyond the scope of this essay. In cholestasJs ('the ultimate

BILE SALT SECRETION i n s u l t t o b i l e acic~ m e t a b o l i s m ' , Pleatorl (19761) t h e e n t e r o h e p a t i c c i r c u l a t i o n is either reduced or abolished, with almost all o f t h e b i l e s a l t p o o l in t h e l a t t e r ins t a n c e b e i n g in t h e w r o n g p l a c e , i.e. in the liver, blood and other tissues. The g a i n i n g of f u r t h e r k n o w l e d g e of b i l e s a l t s e e r e t i o n r t o g e t h e r w i t h its i n f l u e n c e on o t h e r c o m p o n e n l s of b i l e f o r m a l i o n , m a y l e a d t o a b e t t e r u n d e r s t a n d i n g c f intrah e p a t i c c h o l e s t a s i s a n d to t h e m e a n s whereby this serious disorder may be a~feviated. R~ferences AcCatino, L. and Simon. F, R 1976, Identificatiot~ and eharacfer, zat~on of a bile acid receptor in i~Mated hver surface membranes. J. olin. I~lvest 57, 496. Barnhart. J., Ritt. D., Ware, A. and Combos, B. 1973. A c~mpariso~ of the effects of tauroohalate end theophy[line on BSP excretion in dogs. In The Liver: Quantitative Aspects of Structure and Funet,on, e d G. Paumgartner an~ R. Pre,s,g. Basel : K&rger pP 315-325. 8issel, D. k~., Deal, O. R, and Hammaker, L. E. 1975. Determinants of bilirubin Ranspor[ into e,te. Gaseoente~olegy 69. A-S/809. Callahan, E. W. and Schmld, R 1869. Factors erbanemg the bHiary excretion of unconjlJgated bl[irub,n. Gastroenterology 56, 399. C~ey M. C. and Small. D. M 1872. Mioelle formation by blJe salts, A r c h ~ntern Mad. 130 506. Combos. B, 1964. Excretory function of the liver, tn The Liver, Morphology. Bioohem,~try, Pbyslolcgy, ed. Oh. Roulller. New York Academic Press. VoL 2 pp. 11-13 Conway, E. ,J 1960. Critical energy barr]ers in t~e excret,on of ~od,um Nature 187, 394. Cor~way E. J., Ke~an, R, P and 2aduna,sky, J. A. 1961 The sodium pump in skeletal muscle m relal,on to e~ergy barriers J. Physiob florid ]. 155 263. Cowen, A. E. Korman. M. G . Nofmann. A. F and Thomas, P. J 1975 Plasma d~sappearanee of radioactiv,ty after intravenous ,njection of labelled bile acids m m a n Gastroenterology 66, 1567 Diamond, d M. and Tormey. MoB, d. 1966. Studlea on t~e slr~ctural basis of water transport across ebilhelial membranes. Fedn PROD. 25 1458. Dowling. R H. 1972. The enterohepabc circulation. Gastroenterology 62, 1~2. Erlinger. S. and Dhumeaux, O 1974. MechamSms and control of adoration of bile ~ater and electrolytes. Gastroenterology aS. 26~ Erlinoer, S ane Dumonf. M. 1973. lrt~luel~ea of can~licular b,le ~low on sullobrempbthalein transport max,mum in bile in the dog. in The

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Liv@r; Quant,rative Aspects of Structule and Function. ed. G Paumgartner and R preisig Ba~e~: Karger pp. 306~314. Forker, E. L. and G,b~on, G. 1973, Interaction between suffbromophthalein (BSP) and taurochOlate [n The Liver: Quantitative As#acts of Structure and Function, ed. G. Paumgartner anQ R, Preis,g. Basel ; Karger, Pp. 326-33B. GLbson, G E. and Forker, E. L. 1974. Can~dicular bile flow snd bromsulfophthalein transport maximum: ~he effect of a bile sa[t independent choleretic, QC-2644. GastroenterOlogy 66. 1049. Glaslnovic, J C. DumonE M., Dural, M. and ErI,nger, S. 1975(a). Hepato-ceLiular uptake of bile acids ,q the dog: evidence for a common carrier-reed,areal ~ransport syslem. G@stroeatelelegy 69, 973 Glasinewc. J C., Dumunb M., Dural, M and Erl,nger, S 1975(b). Hepato-eeilu]ar uptake of taurochocate in the dog. J. olin invest, 55, 419. Gore~ky, C A and Kluger. S. W. 1969. The relatlon betWeen bile flow and the tramsport maximum for bilirubin it1 the dog. Gastroenterology 56, 398. Gregory, D H,, V]ahcevic, Z. R., Schatzki, P and SwaB, L 1975. Mechanism of seeretlon of biliary liplds [. Rote of bile canalicular and microsomal membranes in the synthesis and transport ef b,liary lecithin and cholesterol. J. e}in Invest. 55. 105, GroOm. H. ~nd Popper. H. 197I. Bepalic b,Ie acids 81let bile duet ligation ,n ra1~ Fedn Proc 30. 534, Hasten, K W ;976. Clmical aspects of bile acid matabohSm, In Recent A~vances in Gastroenterology NO. 3. ed I. A. D. Souchler. Edinburgh" Qhurenlfl-LiVlngstone. pp. 199230. Hofma~n, A, F. 1976. The enteronepatic crrculalion of bile acids in man Advances in Intern. Med. Vo~ 21. e d G. H. Stollerman. pp. 501-534. Jo~DhSOn S. 1941. The circulation of the bile acids in connection with their production con jugat,on and excretion. Physi01, RaY. 21, 493 Korman M Q.. La Russo, N. F., Hoffman. N E and Hofmann. A F. 1975. Development of an ~qtfavenoLls bi~e Act(~ tateranoe teal. New Eng. J. Med. 292* 1205 La Russo N F Holfman, N E., Hofmann. A F and Korma~ M. G. 1975. Validity and sensibvity of an intravenous b~le ac,d tolerance lest ,n pat,eats with liver di~ase. New Eng J Mad. 292, 1209 O'M&ille, E. R. L. and Richards T. G. 1976. The ~cretory characteristics of debydrocholate in the dog : compar, soq w~th the natulal bile salts. J. Physiol (Load.) 261 337. O'M&il[e, E B L and Richards, T. G. 1977 Possible explanations for the difference8 ,q secretory characteristics between COnjugated and free bile acids. J Physiol. ( b o n d ) . 265. 866. O'M&l[[e E. B. L., Ricbards. T. G. and Short A. H. 1965 Acute taurine deplebon and max,real rates ot hepahc conjugabon and seCrelion ol

IRISH JOURNAL OF MEDICAL SCIENCE cholic acid in the dog. J. Physiol. (Lend.). 180, 67. O'M&ige, E. R. L., Richarde, T. G. and Short, A. H. 1966. Factors determining the maximal rate of organic anion secretion by the liver and further evidence on the hepatic site of action of the hormone secretin. J. Physiol. (Lend.). 186, 424. O'M&iJle, E. R. L,, Richards, T. G, and Short, A. H. 1967. T~le influence of conjugation of ohOlie acid on ~ts uptake and secretion : hepatic extraction of tauroebolate and chelate in the dog. J. Physiol (Lend.). 189, 337. O M~i[le, E. Ft. L., Richards, T, G, and Short, A. H. 1969. Obse~at[ons on the elimination rates of single injections of taurocho[ate and chelate in the dog. Q. JI. exp. Physiol. 54, 296. Paumgartner, G,, Sauter, K., Schwarz, H P. and Herz, R. 1973. Hepatic excretory transport maximum for free and conjugated chelate in the rat. Effect of enzyme inducgon. In The Uver: Quantitative aspects of Structure and Function, ed, G. Paumgartner and R. Preisig. Basel : Karger. pp. 337-344. RJchards, T. G. 1965. The plasma concentration of Bromosu]pharein (B.S.P.) after single intravenoua injection in normal and abnormal human subjects. In The Gilrary System, ed. W. Taytor. Oxford : Blackwelh pp. 567579. Riehards, T. G. and O'M&ille, E. R. L 1973. The effect of biliary pH on the maxrmum excretory ~ate of free chelate Fn the dog. In The Liver : Quantitative aspects of Structure and Function,

ed. G, Paumgartner and R. PreisJg. Gasel: Karger, pp. 345-354. Short, A. H. 1969. Clinical use of a compartmental bromsulpbthaie]n test of liver function. M D Thesis. University of Liverpool. Small, D. M, 1971. The physical chemistry of eholan~e acids. In The Bile Acids, Chemistry, Physiology and Metabolism, vol, 1, ed, P. P. Na[r anl G. Kritchevsky. New York London: Ptenum Press. pp. 249-372. Small, D, M., Dowgng. R. H. and Redinger, R N. 1972. The enterohepatic circulation of bile salts. Arch. Intern. Med. 130, 552, Sperber, h 1959. Secretion of organic anions in the ferma30n of urine and bile. Pharmac, Rev. 11. 109 Wagner, G. I., Trotman. B. W. and Scloway, R. 1976. Kinetic analysis o1 bilJary lipid excretion [n man and dog. J. olin. Inve&t. 57, 473. Wannagat, P J., Adler, R. D. and Ockner, R. K. 1976, Enhanced bile salt independent flow associated with augmented bile acid flux; studies of membrane ATPase Gastroenterology 70. A138, 996. Wheeler, H. O. 1972. Secretion of bile acids by the liver and ~heir role in the formation of hepat;c bile. Arch. Intern. Med. 130, 533. Wheeler, 14. O. and King, K. K. 1972. Bi[iary excretion of lecithin and cholesterol Tn the dos. J. olin. invest 51, 1337. Wheeler, H. O., Maneusi-Ungaro. P L. and Whitlock, R. T. 1960. Bile salt transport in the dog. J, olin. rnvest. 39, 1039.

Bile salt secretion.

BILE SALT SECRETION E. R. L, O'M~ille Department of Physiology, University of Liverpool, Liverpoo! L69 9BX. IT is well established that bile formatio...
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