Received for publication April 12, 2005.
Revised September 12, 2005.
Accepted for publication September 12, 2005.

RXRalpha Regulates the Expression of Glutathione S-Transferase Genes and Modulates Acetaminophen-Glutathione Conjugation in Mouse Liver

Abstract

Nuclear receptors, including constitutive androstane receptor, pregnane X receptor, and retinoid X receptor (RXR), modulate acetaminophen-induced hepatotoxicity by regulating the expression of phase I cytochrome P450 (Cyp) 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 RXRalpha in phase II enzyme-mediated detoxification of APAP. Wild type and hepatocyte-specific RXRalpha knockout mice were treated with a toxic dose of APAP (500 mg/kg, ip). Mutant mice were protected from APAP-induced hepatotoxicity, even though basal liver glutathione (GSH) levels were significantly lower in mutant mice when compared to wild type mice. HPLC analysis of APAP metabolites revealed significantly greater levels of APAP-GSH conjugates in livers and bile of mutant mice compared with that of wild type mice. Furthermore, hepatocyte RXRalpha deficiency altered the gene expression profile of the glutathione S-transferase (Gst) family. Basal expression of 13 out of 15 Gst genes studied was altered in hepatocyte-specific RXRalpha-deficient mice. This likely led to enhanced APAP-GSH conjugation and reduced accumulation of N-acetyl-p-benzoquinone imine (NAPQI), a toxic electrophile which is produced by biotransformation of APAP by phase I Cyp enzymes. In conclusion, the data presented in this study define an RXRalpha-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 RXRalpha-mediated pathways.

Key words: Glutathione S-transferases, Phase II enzymes, Oxidative stress/antioxidants

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