Role of CYP3A and CYP2E1 in alcohol-mediated increases in acetaminophen hepatotoxicity: Comparison of wild-type and Cyp2e1(-/-) mice

Kristina K. Wolf, Sheryl G. Wood, Jenna L. Allard, Jane A. Hunt, Nadia Gorman, Brooke W. Walton-Strong, Juliana G. Szakacs, Su X. Duan, Qin Hao, Michael H. Court, Lisa L. Von Moltke, David J. Greenblatt, Vsevolod Kostrubsky, Elizabeth H. Jeffery, Steven A. Wrighton, Frank J. Gonzalez, Peter R. Sinclair, Jacqueline F. Sinclair

Research output: Contribution to journalArticlepeer-review


CYP2E1 is widely accepted as the sole form of cytochrome P450 responsible for alcohol-mediated increases in acetaminophen (APAP) hepatotoxicity. However, we previously found that alcohol [ethanol and isopentanol (EIP)] causes increases in APAP hepatotoxicity in Cyp2e1(-/-) mice, indicating that CYP2E1 is not essential. Here, using wild-type and Cyp2e1(-/-) mice, we investigated the relative roles of CYP2E1 and CYP3A in EIP-mediated increases in APAP hepatotoxicity. We found that EIP-mediated increases in APAP hepatotoxicity occurred at lower APAP doses in wild-type mice (300 mg/kg) than in Cyp2e1(-/-) mice (600 mg/kg). Although this result suggests that CYP2E1 has a role in the different susceptibilities of these mouse lines, our findings that EIP-mediated increases in CYP3A activities were greater in wild-type mice compared with Cyp2e1(-/-) mice raises the possibility that differential increases in CYP3A may also contribute to the greater APAP sensitivity in EIP-pretreated wild-type mice. At the time of APAP administration, which followed an 11 h withdrawal from the alcohols, alcohol-induced levels of CYP3A were sustained in both mouse lines, whereas CYP2E1 was decreased to constitutive levels in wild-type mice. The CYP3A inhibitor triacetyloleandomycin (TAO) decreased APAP hepatotoxicity in EIP-pretreated wild-type and Cyp2e1(-/-) mice. TAO treatment in vivo resulted in inhibition of microsomal CYP3A-catalyzed activity, measured in vitro, with no inhibition of CYP1A2 and CYP2E1 activities. In conclusion, these findings suggest that both CYP3A and CYP2E1 contribute to APAP hepatotoxicity in alcohol-treated mice.

Original languageEnglish (US)
Pages (from-to)1223-1231
Number of pages9
JournalDrug Metabolism and Disposition
Issue number7
StatePublished - Jul 2007

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science


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