title: Acetaminophen hepatotoxicity precipitated by short-term treatment of rats with ethanol and isopentanol: protection by triacetyloleandomycin.
abstract: 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 synergistic increase in acetaminophen hepatotoxicity, compared with rats treated with either alcohol alone. Here, we investigated the role of CYP3A in acetaminophen hepatotoxicity associated with the combined alcohol treatment. Triacetyloleandomycin, a specific inhibitor of CYP3A, protected rats pretreated with ethanol along with isopentanol from acetaminophen hepatotoxicity. At both 0.25 and 0.5 g acetaminophen/kg, triacetyloleandomycin partially prevented elevations in serum levels of alanine aminotransferase. At 0.25 g acetaminophen/kg, triacetyloleandomycin completely protected 6 of 8 rats from histologically observed liver damage, and partially protected the remaining 2 rats. At 0.5 g acetaminophen/kg, triacetyloleandomycin decreased histologically observed liver damage in 7 of 15 rats. In rats pretreated with ethanol plus isopentanol, CYP3A, measured immunohistochemically, was decreased by acetaminophen treatment. This effect was prevented by triacetyloleandomycin. These results suggest that CYP3A has a major role in acetaminophen hepatotoxicity in animals administered the combined alcohol treatment. We also found that exposure to ethanol along with 0.1% isopentanol for only 3 days resulted in maximal increases in acetaminophen hepatotoxicity by the combined alcohol treatment, suggesting that short-term consumption of alcoholic beverages rich in isopentanol may be a risk for developing liver damage from acetaminophen.
authors.affiliation: Veterans Administration Medical Center, White River Junction, VT 05009, USA. JSINC@dartmouth.edu
authors.forename: J F
authors.initials: JF
authors.lastname: Sinclair
authors.forename: J G
authors.initials: JG
authors.lastname: Szakacs
authors.forename: S G
authors.initials: SG
authors.lastname: Wood
authors.forename: V E
authors.initials: VE
authors.lastname: Kostrubsky
authors.forename: E H
authors.initials: EH
authors.lastname: Jeffery
authors.forename: S A
authors.initials: SA
authors.lastname: Wrighton
authors.forename: W J
authors.initials: WJ
authors.lastname: Bement
authors.forename: D
authors.initials: D
authors.lastname: Wright
authors.forename: P R
authors.initials: PR
authors.lastname: Sinclair
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D018712:Analgesics, Non-Narcotic / Q000633:toxicity; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D056486:Chemical and Drug Induced Liver Injury; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D008107:Liver Diseases / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D008297:Male; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000378:metabolism; D000439:Pentanols / Q000008:administration & dosage / Q000494:pharmacology*; D020011:Protective Agents / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D014217:Troleandomycin / Q000494:pharmacology*
chemical_list: D018712:Analgesics, Non-Narcotic; D065607:Cytochrome P-450 Enzyme Inhibitors; D000439:Pentanols; D020011:Protective Agents; D000082:Acetaminophen; D000431:Ethanol; D003577:Cytochrome P-450 Enzyme System; D014217:Troleandomycin; C029683:isopentyl alcohol; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating