PT  - JOURNAL ARTICLE
AU  - Kakizaki, Satoru
AU  - Karami, Sohrab
AU  - Negishi, Masahiko
TI  - Retinoic Acids Repress Constitutive Active Receptor-Mediated Induction by 1,4-bis[2-(3,5-Dichloropyridyloxy)]benzene of the<em>Cyp2b10</em> Gene in Mouse Primary Hepatocytes
AID  - 10.1124/dmd.30.2.208
DP  - 2002 Feb 01
TA  - Drug Metabolism and Disposition
PG  - 208--211
VI  - 30
IP  - 2
4099  - http://dmd.aspetjournals.org/content/30/2/208.short
4100  - http://dmd.aspetjournals.org/content/30/2/208.full
SO  - Drug Metab Dispos2002 Feb 01; 30
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