Retinoid X receptor α (RXRα) plays a pivotal role in regulating liver metabolism. RXRα-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 RXRα 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 RXRα-deficient mice. The down-regulation of GCLC in RXRα-deficient mice led to 40% and 45% reductions in the rate of glutathione (GSH) synthesis and level of hepatic GSH, respectively. Primary hepatocytes from RXRα-deficient mice were more sensitive to t-butylhydroperoxide-induced oxidative stress. However, GSH diminished RXRα-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 RXRα-deficient mice after APAP administration. Taken together, the data indicate that RXRα centrally regulates both phase I and phase II drug metabolism and detoxification. Regulation of hepatic GSH levels by RXRα is essential to protect hepatocytes from oxidative stress, whereas up-regulation of phase I drug metabolism genes by RXRα may render the liver more sensitive to APAP-induced toxicity.
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