RESUMEN
Retinoid X receptor alpha (RXRalpha) plays a pivotal role in regulating liver metabolism. RXRalpha-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 RXRalpha target genes in mouse liver. Glutamate-cysteine ligase catalytic subunit (GCLC), glutathione S-transferasemu, and glutathione peroxidase 1 were down-regulated in the liver of hepatocyte RXRalpha-deficient mice. The down-regulation of GCLC in RXRalpha-deficient mice led to 40% and 45% reductions in the rate of glutathione (GSH) synthesis and level of hepatic GSH, respectively. Primary hepatocytes from RXRalpha-deficient mice were more sensitive to t-butylhydroperoxide-induced oxidative stress. However, GSH diminished RXRalpha-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 RXRalpha-deficient mice after APAP administration. Taken together, the data indicate that RXRalpha centrally regulates both phase I and phase II drug metabolism and detoxification. Regulation of hepatic GSH levels by RXRalpha is essential to protect hepatocytes from oxidative stress, whereas up-regulation of phase I drug metabolism genes by RXRalpha may render the liver more sensitive to APAP-induced toxicity.
Asunto(s)
Glutatión/metabolismo , Hígado/metabolismo , Receptores de Ácido Retinoico/metabolismo , Factores de Transcripción/metabolismo , Xenobióticos/farmacocinética , Acetaminofén/farmacología , Animales , Sistema Enzimático del Citocromo P-450/metabolismo , Regulación de la Expresión Génica , Hepatocitos/metabolismo , Inactivación Metabólica , Ratones , Ratones Noqueados , Estrés Oxidativo , Receptores X RetinoideRESUMEN
Retinoids are well-characterized differentiation and anti-proliferation agents. The functional role of retinoid x receptor alpha (RXRalpha) in cell proliferation and cell cycle regulation is not well understood. Using human Hep3B cell line, we showed that the mRNA level of RXRalpha was closely associated with cell growth. RXRalpha mRNA expression elevated along with the proliferation of Hep3B cells. This association was most evident in RXRalpha and was also noted with retinoic acid (RA) receptor alpha (RARalpha), but not found in other RARs and RXRs. The expression of RXRalpha and cyclin A mRNA was co-regulated when Hep3B cells were cultured in serum-free medium. The mRNA levels of RXRalpha and cyclin A appeared to be highest in G1/S phase in Hep3B cells treated by aphidicolin. Taken together, our data suggest that RXRalpha may be actively involved in cell proliferation and cell cycle regulation in Hep3B cells.