Alcohol-induced hepatotoxicity: a role for oxygen free radicals.
Perfusion of isolated rat livers with ethanol at a concentration of 2 g/l (%o) resulted in a release of glutamate-pyruvate-transaminase (GPT) and sorbitol dehydrogenase (SDH) into the perfusate as markers of toxicity. Inhibition of alcohol dehydrogenase by 4-methylpyrazole or of aldehyde dehydrogenase by cyanamide totally abolished ethanol hepatotoxicity despite of a severalfold increase in acetaldehyde concentration in the perfusate. Addition of superoxide dismutase or catalase clearly suppressed the ethanol-induced release of GPT and SDH, suggesting that .O2- and H2O2 are involved in this process. Also, chelation of iron ions by means of desferrioxamine displayed a clear inhibitory action, suggesting the involvement of an iron-catalyzed Haber-Weiss-reaction leading to the formation of .OH radicals in the hepatotoxic response to ethanol. Our data suggest that during the metabolism of acetaldehyde primary reactive oxygen species (.O2-, H2O2) are produced which may interact to yield hydroxyl or .OH-like radicals, which possibly represent the hepatotoxic principle of ethanol.
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D000431:Ethanol / Q000633:toxicity*; D005609:Free Radicals; D066298:In Vitro Techniques; D007064:L-Iditol 2-Dehydrogenase / Q000378:metabolism; D007773:Lactates / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D010100:Oxygen / Q000633:toxicity*; D010477:Perfusion; D011773:Pyruvates / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D005609:Free Radicals; D007773:Lactates; D011773:Pyruvates; D000431:Ethanol; D007064:L-Iditol 2-Dehydrogenase; D000410:Alanine Transaminase; D010100:Oxygen