Prevention of acetaminophen-induced hepatotoxicity by acute ethanol administration in the rat: comparison with carbon tetrachloride-induced hepatoxicity.
Acetaminophen-induced hepatotoxicity in the presence of ethanol has not been studied. To evaluate the effect of acute ethanol administration on the hepatoxicity of acetaminophen, young male Sprague-Dawley rats (b. wt. 90--130 g) were fasted for 18 hr and were given ethanol (6 g/kg p.o.) or saline. Six hours after this treatment, the rats were injected with acetaminophen (0.5--1.0 g/kg i.p.). In another group, rats were given ethanol (3 g/kg p.o.) or saline and acetaminophen (1 g/kg i.p.) concomitantly. In both groups, acetaminophen produced hepatic damage in saline controls, whereas ethanol treatment prevented the hepatoxicity as judged by serum enzyme activities, hepatic cytochrome P-450 content and liver histology. In 3-methylcholanthrene-treated animals, acetaminophen (0.25 g/kg)-induced hepatic damage was exacerbated, whereas again ethanol treatment (6 g/kg p.o.) apparently prevented the hepatotoxicity of acetaminophen. In contrast, carbon tetrachloride-induced hepatotoxicity (0.1--0.5 ml/kg i.p.) was markedly increased by acute ethanol administration 6 hr before the drug injection, suggesting that the interaction of ethanol- and drug-induced hepatotoxicity is complex. Because acetaminophen has been shown to produce hepatic injury after its biotransformation to reactive metabolite(s) by mixed-function oxidation, and because ethanol inhibits drug oxidation, it can be postulated that ethanol inhibits the biotransformation of acetaminophen to reactive metabolite(s) resulting in the prevention of hepatotoxicity.
D000082:Acetaminophen / Q000037:antagonists & inhibitors* / Q000633:toxicity; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002252:Carbon Tetrachloride Poisoning / Q000517:prevention & control*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D000431:Ethanol / Q000494:pharmacology*; D005969:Glutamate Dehydrogenase / Q000097:blood; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D051381:Rats
D000082:Acetaminophen; D000431:Ethanol; D008748:Methylcholanthrene; D005969:Glutamate Dehydrogenase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase