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ToxSci Advance Access originally published online on September 29, 2004
Toxicological Sciences 2004 82(2):374-380; doi:10.1093/toxsci/kfh286
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Toxicological Sciences vol. 82 no. 2 © Society of Toxicology 2004; all rights reserved.

Enhanced Acetaminophen Toxicity by Activation of the Pregnane X Receptor

Grace L. Guo*,1, Jeff S. Moffit{dagger},1, Christopher J. Nicol*, Jerrold M. Ward{ddagger}, Lauren A. Aleksunes{dagger}, Angela L. Slitt§, Steven A. Kliewer, Jose E. Manautou{dagger} and Frank J. Gonzalez*,2

* Laboratory of Metabolism, CCR, NCI, NIH, Bethesda, Maryland; {dagger} Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut; {ddagger} Veterinary and Tumor Pathology Section, Center for Cancer Research, NCI, Frederick, Maryland; § Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas; and Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas

Received August 24, 2004; accepted August 25, 2004

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 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 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.

Key Words: PXR; acetaminophen; hepatotoxicity; nuclear receptor.


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