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Enhanced acetaminophen toxicity by activation of the pregnane X receptor

  1. Author:
    Guo, G. L.
    Moffit, J. S.
    Ward, J. M.
    Aleksunes, L. A.
    Slitt, A. L.
    Kliewer, S. A.
    Manautou, J. E.
    Gonzalez, F. J.

  2. Author Address

    NCI, Metab Lab, CCR, NIH, Bethesda, MD 20892 USA. Univ Connecticut, Dept Pharmaceut Sci, Storrs, CT USA. NCI, Vet & Tumor Pathol Sect, Ctr Canc Res, Frederick, MD 21701 USA. Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, Kansas City, KS 66103 USA. Univ Texas, SW Med Ctr, Dept Pharmacol, Dallas, TX 75235 USA Gonzalez, FJ, NCI, Metab Lab, CCR, NIH, Bldg 37,Rm 3106B, Bethesda, MD 20892 USA
    1. Year: 2004
    2. Date: DEC
  2. Journal: Toxicological Sciences
    1. 82
    2. 2
    3. Pages: 374-380
  4. Type of Article: Article
  1. Abstract:

    The pregnane X receptor (PXR) is a ligand-activated transcription factor and member of the nuclear receptor superfamily. Activation of PXR represents an important mechanism for the induction of cytochrome P450 3A (CYP3A) enzymes that can convert acetaminophen (APAP) to its toxic intermediate metabolite, N-acetyl-p-benzoquinone imine (NAPQI). Therefore, it was hypothesized that activation of PXR plays a major role in APAP-induced hepatotoxicity. Pretreatment with the PXR activator, pregnenolone 16alpha-carbonitrile (PCN), markedly enhanced APAP-induced hepatic injury, as revealed by increased serum ALT levels and hepatic centrilobular necrosis, in wild-type but not in PXR-null mice. Further analysis showed that following PCN treatment, PXR-null mice had lower CYP3A11 expression, decreased NAPQI formation, and increased maintenance of hepatic glutathione content compared to wild-type mice. Thus, these results suggest that PXR plays a critical role in APAP-induced hepatic toxicity, probably by inducing CYP3A11 expression and hence increasing bioactivation

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External Sources

  1. View record in Web of Science®
  2. WOS: 000225252300004

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