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Research ArticleArticle

Retinoic Acids Repress Constitutive Active Receptor-Mediated Induction by 1,4-bis[2-(3,5-Dichloropyridyloxy)]benzene of theCyp2b10 Gene in Mouse Primary Hepatocytes

Satoru Kakizaki, Sohrab Karami and Masahiko Negishi
Drug Metabolism and Disposition February 2002, 30 (2) 208-211; DOI: https://doi.org/10.1124/dmd.30.2.208
Satoru Kakizaki
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Sohrab Karami
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Masahiko Negishi
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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

  • 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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Drug Metabolism and Disposition: 30 (2)
Drug Metabolism and Disposition
Vol. 30, Issue 2
1 Feb 2002
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Research ArticleArticle

Retinoic Acids Repress Constitutive Active Receptor-Mediated Induction by 1,4-bis[2-(3,5-Dichloropyridyloxy)]benzene of theCyp2b10 Gene in Mouse Primary Hepatocytes

Satoru Kakizaki, Sohrab Karami and Masahiko Negishi
Drug Metabolism and Disposition February 1, 2002, 30 (2) 208-211; DOI: https://doi.org/10.1124/dmd.30.2.208

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Research ArticleArticle

Retinoic Acids Repress Constitutive Active Receptor-Mediated Induction by 1,4-bis[2-(3,5-Dichloropyridyloxy)]benzene of theCyp2b10 Gene in Mouse Primary Hepatocytes

Satoru Kakizaki, Sohrab Karami and Masahiko Negishi
Drug Metabolism and Disposition February 1, 2002, 30 (2) 208-211; DOI: https://doi.org/10.1124/dmd.30.2.208
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