Mechanism of the preventive effect of ethanol on acetaminophen-induced hepatoxicity.
Acute ethanol administration (6 g/kg p.o.) 6 hr before the injection of acetaminophen (0.5 g/kg i.p.) has been shown to prevent acetaminophen-induced hepatotoxicity in fasted young male Sprague-Dawley rats (b.wt. 90--130 g). By using this experimental model, the mechanism of this effect was studied. Covalent binding of reactive metabolite(s) of acetaminophen to hepatic proteins in vivo was less pronounced in ethanol-treated rats than in saline controls 2 and 6 hr after [3H]acetaminophen injection. Although hepatic reduced glutathione content was not affected by ethanol treatment, acetaminophen-induced depletion of reduced glutathione was partially prevented by ethanol. Urinary excretion of mercapturic acid was also decreased in ethanol-treated rats compared with saline controls. In isolated hepatocytes, ethanol partially prevented acetaminophen-induced depletion of reduced glutathione. These data suggested that ethanol decreases the production of reactive metabolite(s) from acetaminophen. Ethanol treatment did not decrease hepatic content of unmetabolized acetaminophen, the substrate of mixed-function oxidation, nor did it affect microsomal enzymes responsible for acetaminophen biotransformation to reactive metabolite(s). However, ethanol inhibited NADPH-dependent covalent binding of reactive metabolite(s) to microsomal protein as well as acetaminophen-induced spectral change. Thus, prevention of acetaminophen-induced hepatotoxicity by acute ethanol administration may be due to decreased production of reactive metabolite(s), most likely because of direct inhibition by ethanol of the biotransformation of acetaminophen to reactive metabolite(s).
D000082:Acetaminophen / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D001711:Biotransformation; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D000431:Ethanol / Q000097:blood / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D011485:Protein Binding; D051381:Rats
D000082:Acetaminophen; D000431:Ethanol; D005978:Glutathione