Abstract
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.
Footnotes
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Satoru Kakizaki is a JSPS (Japan Society for the Promotion of Science Research) fellow. Sohrab Karami is a recipient of a fellowship from Centrala Studie Nämnden International, Sweden.
- Abbreviations used are::
- P450
- cytochrome P450
- CAR
- constitutive active receptor
- PB
- phenobarbital
- RXR
- retinoid X receptor
- PBREM
- phenobarbital-responsive enhancer module
- RAR
- retinoid acid receptor
- DMSO
- dimethyl sulfoxide
- TCPOBOP
- 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene
- tk
- thymidine kinase
- RT-PCR
- reverse transcriptase-polymerase chain reaction
- GAPDH
- glyceraldehyde-3-phosphate dehydrogenase
- mCAR
- mouse CAR
- RA
- retinoic acid
- Received July 31, 2001.
- Accepted November 9, 2001.
- U.S. Government
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