Toxicology Letters, 63 (1992) 221-229 0 1992 Elsevier Science Publishers B.V. All rights reserved 0378-4274/92/$5.00

227

TOXLET 02819

Commentary

Commentary on ‘ethanol toxicity and oxidative stress’ by S.C. Bondy

Lester A. Reinke Department of Pharmacology, University of Oklahoma Health Sciences Center, Oklahoma City, OK (USA)

(Received 21 August 1992) (Accepted 21 August 1992)

The first evidence that free radicals might be involved in the toxicity of ethanol is usually attributed to DiLuzio [ 11,who reported lipid peroxidation in livers of rats that were given large acute doses of alcohol. These early observations have been confirmed by studies from many laboratories. Because free radicals attack polyunsaturated fatty acids in lipid membranes, lipid peroxidation is often interpreted as evidence that radicals have been generated. Spin trapping and EPR spectroscopy have provided direct evidence that lipid radicals are indeed generated after the acute [2,3] and chronic [4] administration of ethanol to experimental animals. These lipid radicals are thought to be intermediates of lipid peroxidation, but are probably secondary radicals formed after the attack of an initial more reactive intermediate. However, the nature of the initial radical(s) is still uncertain. Spin trapping and EPR spectroscopy studies have shown that ethanol is metabolized to the 1-hydroxyethyl radical in liver microsomes and in vivo [3-51, suggesting that this intermediate may have a role in alcohol toxicity. It should be noted that the 1-hydroxyethyl radical is a known product of hydroxyl radical attack on ethanol, and recent EPR studies have examined this relationship in microsomal preparations [6]. In addition, other iron-oxygen complexes are capable of abstracting a hydrogen atom from ethanol to form the 1-hydroxyethyl radical [7]. Thus, the demonstration

Correspondence to: Lester A. Reinke, Department of Pharmacology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73190, USA.

228

that I-hydroxyethyl radicals are formed does not preclude the possible involvement of reactive oxygen intermediates in alcohol toxicity. Most available data which implicates a role of oxidative stress in ethanol toxicity is unfortunately indirect. In general terms, it consists of the description of a phenomenon which could result from free radical generation (e.g., lipid peroxidation), a protective effect of antioxidants, and partial protection by agents which are thought to specifically chelate iron or to inhibit enzymes which can produce reactive oxygen intermediates. Alternatively, alcohol may be shown to alter the activity of enzymes which either generate oxygen radicals as metabolites (e.g., P-450 enzymes or xanthine oxidase), or which protect tissues against oxidative damage (e.g., superoxide dismutase). Taken together, the data are consistent with the hypothesis of ethanolinduced oxidative stress in vivo. However, as Dr. Bondy repeatedly points out in the review which follows, there are other possible interpretations of all of these data. Unfortunately, there are currently no unambiguous methods for the detection of oxygen radicals in intact cells in vivo or in vitro. Until such methods can be developed, the role of reactive oxygen species in alcoholic tissue damage will remain speculative. Finally, it might be asked whether the term ‘oxidative stress’ appropriately describes the series of events associated with ethanol administration. Oxidative stress is often defined as a condition resulting from the formation of reactive oxygen species, and there is indeed evidence that this may occur during alcohol intoxication. However, another definition of oxidative stress is ‘a disturbance in the prooxidant-antioxidant balance in favor of the former’ [8]. Although the hydroxyl radical is a powerful oxidant, its formation in vivo during ethanol intoxication is uncertain. Dr. Bondy has cited several lines of evidence for the involvement of superoxide and I-hydroxyethyl radicals, but these species tend to be reducing intermediates. Furthermore, high intracellular levels of NADH resulting from the metabolism of ethanol and acetaldehyde may be involved in alcohol toxicity, but these are clearly ‘reductive’ conditions. Is it possible that ‘reductive stress’ is a more appropriate term to describe the conditions associated with alcohol toxicity? REFERENCES 1 DiLuzio,

N.R. (1964) Prevention

of the acute ethanol-induced

tion of anti-oxidants. Life Sci. 3. 113-l 19. 2 Reinke, L.A., Kotake. Y., McCay, P.B. and Janzen,

fatty liver by the simultaneous

E.G. (1991) Spin-trapping

radicals formed following the acute administration of ethanol radicals with PBN. Free Rad. Biol. Med. 11, 31-39. 3 Knecht, K.T., Bradford, B.U., Mason, R.P. and Thurman,

rats: correlation

with radical

of

formation

free radical

free

1-hydroxyethyl

(1990) In vivo formation

radical metabolite of ethanol. Mol. Pharmacol. 38, 2630. 4 Reinke, L.A., Lai, E.K., DuBose, C.M. and McCay, P.B. (1987) Reactive in heart and liver of ethanol-fed USA 84, 922339227.

studies of hepatic

to rats: in vivo detection R.G.

administra-

generation

of a free in vivo

in vitro. Proc. Natl. Acad.

5 Albano, E., Tomasi. A., Goria-Gatti, L. and Dianzani, M.U. (1988) Spin trapping of free radical produced during the microsomal metabolism of ethanol. Chem. Biol. Interact. 65, 223-234.

Sci.

species

229

6 McCay, P.B., Reinke, L.A. and Rau, J.M. (1992) Hydroxyl radicals are generated by hepatic microsomes during NADPH oxidation: relationship to ethanol metabolism. Free Rad. Res. Commun. 15, 335-346. 7 Rush, J.D. and Koppenol, W.H. (1986) Oxidizing intermediates in the reaction of ferrous EDTA with hydrogen peroxide. J. Biol. Chem. 261,6730-6733. 8 Sies, H. (1985) Oxidative stress: introductory remarks. In: H. Sies (Ed.), Oxidative Stress, Academic Press, London, pp. l-8.

Commentary on 'Ethanol toxicity and oxidative stress' by S.C. Bondy.

Toxicology Letters, 63 (1992) 221-229 0 1992 Elsevier Science Publishers B.V. All rights reserved 0378-4274/92/$5.00 227 TOXLET 02819 Commentary C...
156KB Sizes 0 Downloads 0 Views