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ToxSci Advance Access published online on September 29, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh286
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received August 24, 2004
Accepted August 25, 2004

Biotransformation and Toxicokinetics

Enhanced Acetaminophen Toxicity by Activation of the Pregnane X Receptor

Grace L. Guo 1, Jeff Moffit 2, Christopher J. Nicol 1, Jerrold M. Ward 3, Lauren Aleksunes 2, Angela Slitt 4, Steve A. Kliewer 5, Jose Manautou 2, and Frank J. Gonzalez 1*

1 Laboratory of Metabolism, CCR, NCI, NIH, Bethesda, MD
2 Department of Pharmacology, University of Connecticut, Storrs, CT
3 Veterinary and Tumor Pathology Section, Center for Cancer Research, NCI, Frederick, MD
4 Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS
5 Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX

* To whom correspondence should be addressed. E-mail: fjgonz{at}helix.nih.gov.


  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 (NAPQ I). Therefore, it was hypothesized that activation of PXR plays a major role in APAP-induced hepatotoxicity. Pretreatment with the PXR activator, pregnenolone 16{alpha}-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 NAPQ I formation and increased maintenance of hepatic glutathione content compared to wild-type mice. Thus, these results suggest PXR plays a critical role in APAP-induced hepatic toxicity, probably by regulating CYP3A11 expression and hence increasing bioactivation.

Keywords: PXR; acetaminophen; hepatotoxicity; nuclear receptor.
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