Increased acetaminophen-induced hepatotoxicity after chronic ethanol consumption in mice

The effect of chronic ethanol consumption on acetaminophen (200, 400, and 600 mg/kg) toxicity was determined by maintaining mice for 10 days on diets consisting of chow and one of the following drinking solutions: 10% ethanol + 10% sucrose, 8% sucrose, or tap water. Toxicity as manifested by mortality, liver enlargement, and liver congestion was greatest in the ethanol-treated group. We suggest that the greater mortality was a result of the increased liver congestion and consequent hypovolemia. Despite the increased levels of cytochrome(s) P-450, covalent binding of ³H]acetaminophen reactive metabolite(s) to liver protein was not higher in ethanol-treated animals. This can be explained by the higher initial glutathione concentration and/or ability to replenish glutathione in the ethanol-treated group. We suggest that the enhancement of acetaminophen toxicity by ethanol is the result of an effect of ethanol on hepatocyte membranes which renders the cells more susceptible to toxic injury.