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Drug Metabolism and Disposition Fast Forward
First published on September 1, 2005; DOI: 10.1124/dmd.105.005256

0090-9556/05/3312-1827-1836$20.00
DMD 33:1827-1836, 2005

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ROLE OF THE NUCLEAR RECEPTOR PREGNANE X RECEPTOR IN ACETAMINOPHEN HEPATOTOXICITY

Kristina K. Wolf, Sheryl G. Wood, Jane A. Hunt, Brooke W. Walton-Strong, Kazuto Yasuda, Lubin Lan, Su X. Duan, Qin Hao, Steven A. Wrighton, Elizabeth H. Jeffery, Ronald M. Evans, Juliana G. Szakacs, Lisa L. von Moltke, David J. Greenblatt, Michael H. Court, Erin G. Schuetz, Peter R. Sinclair, and Jacqueline F. Sinclair

Departments of Pharmacology and Toxicology (K.K.W., P.R.S., J.F.S.) and Biochemistry (B.W.W.-S., P.R.S., J.F.S.), Dartmouth Medical School, Hanover, New Hampshire; Veterans Affairs Medical Center, White River Junction, Vermont (S.G.W., J.A.H., P.R.S., J.F.S.); Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (K.Y., L.L., E.G.S.); Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, Massachusetts (S.X.D., Q.H., L.L.v.M., D.J.G., M.H.C.); Department of Drug Disposition, Lilly Research Laboratories, Indianapolis, Indiana (S.A.W.); Department of Food Science and Human Nutrition, University of Illinois, Urbana, Illinois (E.H.J.); Gene Expression Laboratory, the Salk Institute for Biological Studies, Howard Hughes Medical Institute, La Jolla, California (R.M.E.); and Harvard Vanguard Medical Associates, Boston, Massachusetts (J.G.S.)

The pregnane X receptor (PXR) is a transcriptional regulator of xenobiotic metabolizing enzymes, including cytochrome P450 3A (CYP3A), and transporters. Pretreatment of mice and rats with inducers of CYP3A increases acetaminophen (APAP) hepatotoxicity. In untreated mice, the amount of hepatic CYP3A11 mRNA is 4-fold greater in PXR(–/–) mice compared to wild-type mice (Guo et al., 2003), a finding anticipated to increase APAP hepatotoxicity in PXR(–/–) mice. We investigated APAP hepatotoxicity in wild-type and PXR(–/–) mice in a C57BL/6 background, with APAP administered by gavage. Despite a 2.5-fold higher level of total hepatic CYP3A protein and a 3.6-fold higher level of CYP3A activity compared to wild-type mice, PXR(–/–) mice were less sensitive to APAP hepatotoxicity. Hepatic levels of CYP2E1 were identical in the two mouse lines, but hepatic CYP1A2 levels were 3-fold greater in wild-type mice compared to PXR(–/–) mice. Caffeine, an inhibitor of CYP1A2 activity and an enhancer of CYP3A activity, decreased APAP hepatotoxicity in wild-type mice. APAP uptake was 1.5-fold greater in wild-type mice compared to PXR(–/–) mice. No significant differences in the formation of APAP glucuronide and sulfate-conjugated metabolites were observed between wild-type and PXR(–/–) mice. Glutathione levels were similar in the two mouse lines and were transiently decreased to similar amounts after APAP administration. Our finding that APAP hepatotoxicity was decreased in PXR(–/–) mice indicates that PXR is an important modulator of APAP hepatotoxicity, through positive modulation of constitutive CYP1A2 expression and possibly through increased APAP absorption.

Address correspondence to: Dr. Jacqueline Sinclair, Research 151, Veterans Administration Medical Center, White River Junction, VT 05009. E-mail: JSINC{at}dartmouth.edu




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