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Retinoid X Receptor Regulates the Expression of Glutathione S-transferase Genes and Modulates Acetaminophen-Glutathione Conjugation in Mouse Liver

Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas

Nuclear receptors, including constitutive androstane receptor, pregnane X receptor, and retinoid X receptor (RXR), modulate acetaminophen (APAP)-induced hepatotoxicity by regulating the expression of phase I cytochrome P450 (P450) genes. It has not been fully resolved, however, whether they regulate APAP detoxification at the phase II level. The aim of the current study was to evaluate the role of RXR in phase II enzyme-mediated detoxification of APAP. Wild-type and hepatocyte-specific RXR knockout mice were treated with a toxic dose of APAP (500 mg/kg i.p.). Mutant mice were protected from APAP-induced hepatotoxicity, even though basal liver glutathione (GSH) levels were significantly lower in mutant mice compared with those of wild-type mice. High-performance liquid chromatography analysis of APAP metabolites revealed significantly greater levels of APAP-GSH conjugates in livers and bile of mutant mice compared with those of wild-type mice. Furthermore, hepatocyte RXR deficiency altered the gene expression profile of the glutathione S-transferase (Gst) family. Basal expression of 13 of 15 Gst genes studied was altered in hepatocyte-specific RXR-deficient mice. This probably led to enhanced APAP-GSH conjugation and reduced accumulation of N-acetyl-p-benzoquinone imine, a toxic electrophile that is produced by biotransformation of APAP by phase I P450 enzymes. In conclusion, the data presented in this study define an RXR-Gst regulatory network that controls APAP-GSH conjugation. This report reveals a potential novel strategy to enhance the detoxification of APAP or other xenobiotics by manipulating Gst activity through RXR-mediated pathways.

Address correspondence to: Dr. Yu-Jui Yvonne Wan, Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160-7417. E-mail: ywan{at}kumc.edu

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