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Drug Metabolism and Disposition Fast Forward
First published on March 28, 2007; DOI: 10.1124/dmd.107.014738

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Received for publication January 11, 2007.
Revised March 26, 2007.
Accepted for publication March 26, 2007.

Role of CYP3A and CYP2E1 in Alcohol-Mediated Increases in Acetaminophen Hepatotoxicity: Comparison of Wild-Type and Cyp2e1(-/-) Mice

Kristina K. Wolf 1, Sheryl G. Wood 2, Jenna L. Allard 2, Jane A. Hunt 2, Nadia Gorman 1, Brooke W. Walton-Strong 1, Juliana G. Szakacs 3, Su X. Duan 4, Qin Hao 5, Michael H. Court 5, Lisa L. von Moltke 5, David J. Greenblatt 5, Vsevolod Kostrubsky 6, Elizabeth H. Jeffery 7, Steven A. Wrighton 8, Frank J. Gonzalez 9, Peter R. Sinclair 10, Jacqueline F. Sinclair 11*

1 Dartmouth Medical School 2 VA Medical Center White River Junction, VT 3 Harvard Vanguard Medical Associates 4 Tufts University of Medical School and Tufts New England Medicine Center 5 Tufts University School of Medicine and Tufts New England Medical Center 6 Pfizer Global Research and Development 7 University of Illinois 8 Lilly Research Laboratories 9 National Cancer Institute 10 VA Medical Center White River Junction, VT and Dartmouth Medical School 11 Dartmouth University

* Address correspondence to: E-mail: jsinc{at}dartmouth.edu

Abstract

CYP2E1 is widely accepted as the sole form of cytochrome P450 (CYP) 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 to 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, while 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.


Key words: CYP expression, CYP2E, CYP3A, cytochrome P450, drug-induced hepatotoxicity, hepatotoxicity, liver toxicity, transgenic models


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