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Retinoid X Receptor Regulates Glutathione Homeostasis and Xenobiotic Detoxification Processes in Mouse Liver

Department of Pathology, Harbor-University of California Los Angeles (UCLA) Research and Education Institute, Torrance, California (Y.W., X.Z., F.B.-G., R.C.V.R., J.A., K.H., S.W.F.); and Division of Gastroenterology and Liver Diseases, University of Southern California (USC) Liver Disease Research Center, USC-UCLA Research Center for Alcoholic Liver and Pancreatic Diseases, Keck School of Medicine USC, Los Angeles, California (L.C., Y.Z., S.C.L.)

Retinoid X receptor (RXR) plays a pivotal role in regulating liver metabolism. RXR-mediated gene expression involved in amino acid metabolism was examined using the NIA Mouse 15K cDNA microarray containing 15,000 different expressed sequence tags. Seven amino acid metabolic genes, three of which encode enzymes involved in phase II detoxification process, were identified as RXR target genes in mouse liver. Glutamate-cysteine ligase catalytic subunit (GCLC), glutathione S-transferaseµ, and glutathione peroxidase 1 were down-regulated in the liver of hepatocyte RXR-deficient mice. The down-regulation of GCLC in RXR-deficient mice led to 40% and 45% reductions in the rate of glutathione (GSH) synthesis and level of hepatic GSH, respectively. Primary hepatocytes from RXR-deficient mice were more sensitive to t-butylhydroperoxide–induced oxidative stress. However, GSH diminished RXR-deficient mice were resistant to acetaminophen (APAP)-induced hepatotoxicity. Analysis of phase I detoxification genes revealed that CYP1A2 and CYP3A11 were up-regulated in wild-type mice but down-regulated in RXR-deficient mice after APAP administration. Taken together, the data indicate that RXR centrally regulates both phase I and phase II drug metabolism and detoxification. Regulation of hepatic GSH levels by RXR is essential to protect hepatocytes from oxidative stress, whereas up-regulation of phase I drug metabolism genes by RXR may render the liver more sensitive to APAP-induced toxicity.

Address correspondence to: Dr. Yu-Jui Yvonne Wan, Department of Pharmacology, Toxicology and Therapeutics, Mail Stop 1018, Breidenthal Building, The University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160-7417. Email: ywan{at}kumc.edu

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