Enhanced acetaminophen toxicity by activation of the pregnane X receptor

Gracel L. Guo, Jeff S. Moffit, Christopher J. Nicol, Jerrold M. Ward, Lauren A. Aleksunes, Angela L. Slitt, Steven A. Kliewer, Jose E. Manautou, Frank J. Gonzalez

Research output: Contribution to journalArticlepeer-review

84 Scopus citations

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 16α-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.

Original languageEnglish (US)
Pages (from-to)374-380
Number of pages7
JournalToxicological Sciences
Volume82
Issue number2
DOIs
StatePublished - Dec 2004

Keywords

  • Acetaminophen
  • Hepatotoxicity
  • Nuclear receptor
  • PXR

ASJC Scopus subject areas

  • Toxicology

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