RT Journal Article SR Electronic T1 Retinoic Acids Repress Constitutive Active Receptor-Mediated Induction by 1,4-bis[2-(3,5-Dichloropyridyloxy)]benzene of theCyp2b10 Gene in Mouse Primary Hepatocytes JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 208 OP 211 DO 10.1124/dmd.30.2.208 VO 30 IS 2 A1 Satoru Kakizaki A1 Sohrab Karami A1 Masahiko Negishi YR 2002 UL http://dmd.aspetjournals.org/content/30/2/208.abstract AB The nuclear orphan receptor constitutive active receptor (CAR) can be activated to induce CYP2B genes by the potent phenobarbital-type inducer 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) in which the receptor forms a heterodimer with the retinoid X receptor (RXR) and binds to a conserved enhancer element NR1. Effects of retinoic acids on the activation of CAR were examined. Treatment with 9-cis- or all-trans-retinoic acid markedly repressed TCPOBOP induction of CYP2B10 mRNA in mouse primary hepatocytes. Both retinoic acids also repressed TCPOBOP-induced NR1 enhancer activity in both transfected hepatocytes and HepG2 cells. Moreover, coexpression of the retinoic acid receptor (RAR) increased the repression in the cotransfected HepG2 cells, whereas that of RXR decreased the repression. Thus, the increased heterodimerization of RXR with RAR by retinoic acid treatment seemed to reduce the RXR available for CAR heterodimerization, resulting in the repression of CAR activity. This type of nuclear receptor signaling may play an important role as a modulator in the CYP2B regulation. U.S. Government