Increased hepatotoxicity of acetaminophen after chronic ethanol consumption in the rat.
This study was undertaken to evaluate the effects of chronic ethanol consumption on the hepatotoxicity of acetaminophen. Male Sprague-Dawley rats were pair fed a nutritionally adequate liquid diet containing either ethanol or isocaloric carbohydrate for 4-6 wk. Acetaminophen (0.5 g/kg body wt) was given intraperitoneally 12 h after ethanol withdrawal. By 36 h, frank hepatic centrilobular necrosis and a decrease in hepatic aminopyrine N-demethylase activity were observed in the ethanol-fed rats, whereas in controls the changes were minimal. Serum glutamyl oxaloacetic transaminase and glutamate dehydrogenase activities were significantly increased in ethanol-fed rats. Hepatic damage in ethanol fed rats was apparent already at 6 h, as evidenced by elevated serum enzyme activities and ultrastructural changes, particularly of the mitochondria. The depletion of hepatic glutathione content and the covalent binding of acetaminophen metabolite(s) were significantly greater in ethanol-fed rats than in controls. Urinary excretion of mercapturic acid conjugate during the first 12 h was also increased in ethanol-fed rats. In an in vitro study, covalent binding of acetaminophen metabolite(s) to microsomal protein was increased after ethanol feeding for 4-6 wk. Thus, chronic ethanol feeding increases the hepatotoxicity of acetaminophen; enhanced production of reactive metabolite(s) may be responsible.
D000082:Acetaminophen / Q000633:toxicity*; D000437:Alcoholism / Q000150:complications*; D000633:Aminopyrine N-Demethylase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D004347:Drug Interactions; D000431:Ethanol / Q000494:pharmacology; D005969:Glutamate Dehydrogenase / Q000097:blood; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051381:Rats
D000082:Acetaminophen; D000431:Ethanol; D005969:Glutamate Dehydrogenase; D000633:Aminopyrine N-Demethylase; D001219:Aspartate Aminotransferases; D005978:Glutathione