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

Drug Metab Dispos. 2007 Jul;35(7):1223-31. doi: 10.1124/dmd.107.014738. Epub 2007 Mar 28.


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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetaminophen
  • Alanine Transaminase / blood
  • Animals
  • Benzoquinones / metabolism
  • Chemical and Drug Induced Liver Injury*
  • Cytochrome P-450 CYP1A2 / metabolism
  • Cytochrome P-450 CYP2E1 / deficiency
  • Cytochrome P-450 CYP2E1 / genetics
  • Cytochrome P-450 CYP2E1 / metabolism*
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / biosynthesis
  • Cytochrome P-450 Enzyme System / metabolism*
  • Disease Models, Animal
  • Drug Synergism
  • Enzyme Induction / drug effects
  • Enzyme Inhibitors / pharmacology
  • Ethanol / toxicity*
  • Glucuronides / metabolism
  • Glutathione / metabolism
  • Hydroxylation
  • Imines / metabolism
  • Liver / drug effects*
  • Liver / enzymology*
  • Liver / pathology
  • Liver Diseases / metabolism
  • Liver Diseases / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Pentanols / toxicity*
  • Severity of Illness Index
  • Testosterone / metabolism
  • Troleandomycin / pharmacology


  • Benzoquinones
  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • Glucuronides
  • Imines
  • Pentanols
  • Acetaminophen
  • Ethanol
  • Testosterone
  • Cytochrome P-450 Enzyme System
  • Troleandomycin
  • isopentyl alcohol
  • Cytochrome P-450 CYP2E1
  • CYP3A protein, mouse
  • Cytochrome P-450 CYP1A2
  • Cytochrome P-450 CYP3A
  • Alanine Transaminase
  • N-acetyl-4-benzoquinoneimine
  • Glutathione