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

Jacqueline F. Sinclair, Juliana G. Szakacs, Sheryl G. Wood, Vsevolod E. Kostrubsky, Elizabeth H. Jeffery, Steven A. Wrighton, William J. Bement, Dane Wright, Peter R. Sinclair

Research output: Contribution to journalArticlepeer-review

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. Copyright (C) 2000 Elsevier Science Inc.

Original languageEnglish (US)
Pages (from-to)445-454
Number of pages10
JournalBiochemical Pharmacology
Volume59
Issue number4
DOIs
StatePublished - Feb 15 2000

Keywords

  • Acetaminophen hepatotoxicity
  • Alcohols
  • CYP3A
  • Ethanol and acetaminophen
  • Isopentanol
  • Short-term alcohols
  • Triacetyloleandomycin

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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