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

• DOI: 10.1124/mol.65.3.550
• Publication Date: 2004-02-20T01:34:06Z
• Authors: Yong Wu; Xiaoxue Zhang; Fawzia Bardag-Gorce; Rose C.V. Robel; Jonathan Aguilo; Lixin Chen; Ying Zeng; Kelly Hwang; Samuel W. French; Shelly C. Lu; Yu-Jui Y. Wan
• Keywords: GSTP1; Constitutive androstane receptor; Retinoid X receptor

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