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

Abstract

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-transferase, 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 APAPinduced toxicity.

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

“…Constitutive androstane receptor (CAR) and pregnane X receptor (PXR) function as critical regulators of APAP metabolism and hepatotoxicity by regulating expression of phase I P450 genes involved in APAP bioactivation (Zhang et al, 2002;Guo et al, 2004). We reported previously that RXR␣ modulates APAP-induced liver injury by regulating mRNA levels of P450 genes, which participate in APAP bioactivation (Wu et al, 2004b). In the present report, we demonstrate that hepatocyte RXR␣ also modulates APAP detoxification by altering phase II enzyme-mediated conjugation of APAP.…”

“…Using hepatocytespecific RXR␣ knockout mice, we demonstrated previously that the level of RXR␣ is crucial for maintaining homeostasis of cholesterol, fatty acids, and carbohydrates as well as for the metabolism of xenobiotics (Wan et al, 2000a(Wan et al, ,b, 2003Dai et al, 2003;Wu et al, 2004a). Absence of RXR␣ in hepatocytes alters the hepatic expression profile of genes, including phase I and II enzymes critical for xenobiotic metabolism (Wu et al, 2004b).…”

Regulation of glutathione synthesis

“…Another example where GCLC and GS are coordinately regulated but GCLM is unchanged is found in liver-specific retinoid X receptor α (RXRα) knockout mice (Wu et al, 2004). RXR are members of the nuclear receptor family that regulate diverse developmental and physiological processes by binding to DNA response elements and modulating transcriptional activity (Wan et al, 2000).…”

Rosiglitazone attenuates suppression of RXRα-dependent gene expression in inflamed liver

“…RXRα is the most highly expressed RXR isoform in the liver and plays a central role in regulating major physiological processes in the liver, including endobiotic/xenobiotic metabolism and homeostasis [12,13]. We have recently demonstrated that reduction of nuclear RXRα protein levels by LPS administration in vivo and IL-1β in vitro, appear to be a major contributor to the repression of hepatic genes during the negative hepatic APR [14][15][16].…”