TY - JOUR T1 - Role of CYP3A and CYP2E1 in Alcohol-Mediated Increases in Acetaminophen Hepatotoxicity: Comparison of Wild-Type and <em>Cyp2e1</em>(–/–) Mice JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1223 LP - 1231 DO - 10.1124/dmd.107.014738 VL - 35 IS - 7 AU - Kristina K. Wolf AU - Sheryl G. Wood AU - Jenna L. Allard AU - Jane A. Hunt AU - Nadia Gorman AU - Brooke W. Walton-Strong AU - Juliana G. Szakacs AU - Su X. Duan AU - Qin Hao AU - Michael H. Court AU - Lisa L. von Moltke AU - David J. Greenblatt AU - Vsevolod Kostrubsky AU - Elizabeth H. Jeffery AU - Steven A. Wrighton AU - Frank J. Gonzalez AU - Peter R. Sinclair AU - Jacqueline F. Sinclair Y1 - 2007/07/01 UR - http://dmd.aspetjournals.org/content/35/7/1223.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -