Acetaminophen hepatotoxicity precipitated by short-term treatment of rats with ethanol and isopentanol - Protection by triacetyloleandomycin

Ethanol and isopentanol are the predominant alcohols in alcoholic beverages . We have reported previously that pretreatment of rats with a liquid diet containing 6.3% ethanol plus 0.5% isopentanol for 7 days results in a syner gistic increase in acetaminophen hepatotoxicity, compared with rats treated with either alcohol alone. Here, we investigated the role of CYP3A in acet aminophen hepatotoxicity associated with the combined alcohol treatment. Tr iacetyloleandomycin, a specific inhibitor of CYP3A, protected rats pretreat ed with ethanol along with isopentanol from acetaminophen hepatotoxicity. A t both 0.25 and 0.5 g acetaminophen/kg, triacetyloleandomycin partially pre vented elevations in serum levels of alanine aminotransferase. At 0.25 g ac etaminophen/kg, triacetyloleandomycin completely protected 6 of 8 rats from histologically observed liver damage, and partially protected the remainin g 2 rats. At 0.5 g acetaminophen/kg, triacetyloleandomycin decreased histol ogically observed liver damage in 7 of 15 rats. In rats pretreated with eth anol plus isopentanol, CYP3A, measured immunohistochemically, was decreased by acetaminophen treatment. This effect was prevented by triacetyloleandom ycin. These results suggest that CYP3A has a major role in acetaminophen he patotoxicity in animals administered the combined alcohol treatment. We als o found that exposure to ethanol along with 0.1% isopentanol for only 3 day s resulted in maximal increases in acetaminophen hepatotoxicity by the comb ined alcohol treatment, suggesting that short-term consumption of alcoholic beverages rich in isopentanol may be a risk for developing liver damage fr om acetaminophen. BIOCHEM PHARMACOL 59;4: 445-454, 2000. (C) 2000 Elsevier Science Inc.