Enhancement by glutathione depletion of ethanol-induced acute hepatotoxicity in vitro and in vivo.
Ethanol at initial concentrations between 0.75 and 6 g/l produced a dose-dependent release of the enzymes glutamic-pyruvic-transaminase and sorbitol dehydrogenase (GPT, SDH) from the isolated perfused rat liver. At the concentration of 6 g/l, it also decreased the oxygen consumption and elevated the calcium content of the isolated livers. These toxic effects of ethanol were significantly enhanced in livers, the glutathione content of which had been depleted by pretreatment with phorone. Ethanol-induced toxicity in glutathione-depleted isolated livers could be prevented both by inhibition of alcohol dehydrogenase with 4-methylpyrazole and of xanthine oxidase with allopurinol. In rats, in vivo, 1.6 g/kg ethanol injected intravenously produced a small increase in serum GPT and SDH concentrations 4 h after its administration. This increase in enzyme activities was several-fold higher and longer lasting in rats pretreated with phorone. Glutathione depletion per se did not induce hepatotoxicity in vitro or in vivo. Since glutathione is involved in several lines of defense against oxidative damage, our results of an enhanced susceptibility of glutathione-depleted livers to ethanol toxicity favour the hypothesis that ethanol exerts its hepatotoxic action via an activation of molecular oxygen.
D000410:Alanine Transaminase / Q000378:metabolism*; D000818:Animals; D000431:Ethanol / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D007659:Ketones / Q000494:pharmacology; D007064:L-Iditol 2-Dehydrogenase / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D010101:Oxygen Consumption; D051381:Rats; D011919:Rats, Inbred Strains; D013401:Sugar Alcohol Dehydrogenases / Q000378:metabolism*
D007659:Ketones; D000431:Ethanol; C018637:phorone; D013401:Sugar Alcohol Dehydrogenases; D007064:L-Iditol 2-Dehydrogenase; D000410:Alanine Transaminase; D005978:Glutathione