TY - JOUR T1 - ROLE OF THE NUCLEAR RECEPTOR PREGNANE X RECEPTOR IN ACETAMINOPHEN HEPATOTOXICITY JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1827 LP - 1836 DO - 10.1124/dmd.105.005256 VL - 33 IS - 12 AU - Kristina K. Wolf AU - Sheryl G. Wood AU - Jane A. Hunt AU - Brooke W. Walton-Strong AU - Kazuto Yasuda AU - Lubin Lan AU - Su X. Duan AU - Qin Hao AU - Steven A. Wrighton AU - Elizabeth H. Jeffery AU - Ronald M. Evans AU - Juliana G. Szakacs AU - Lisa L. von Moltke AU - David J. Greenblatt AU - Michael H. Court AU - Erin G. Schuetz AU - Peter R. Sinclair AU - Jacqueline F. Sinclair Y1 - 2005/12/01 UR - http://dmd.aspetjournals.org/content/33/12/1827.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -