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Research ArticleArticle

Histone Deacetylase Inhibitors Induce Cytochrome P450 2B by Activating Nuclear Receptor Constitutive Androstane Receptor

Daichi Takizawa, Satoru Kakizaki, Norio Horiguchi, Hiroki Tojima, Yuichi Yamazaki, Takeshi Ichikawa, Ken Sato and Masatomo Mori
Drug Metabolism and Disposition September 2010, 38 (9) 1493-1498; DOI: https://doi.org/10.1124/dmd.110.032854
Daichi Takizawa
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Satoru Kakizaki
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Norio Horiguchi
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Hiroki Tojima
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Yuichi Yamazaki
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Takeshi Ichikawa
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Ken Sato
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Masatomo Mori
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Abstract

Valproic acid, a histone deacetylase (HDAC) inhibitor, induces the cytochrome P450 2B subfamily. However, the effects of HDAC inhibitors on CYP2B induction are still not fully understood. Nuclear receptor constitutive androstane receptor (CAR) is a key regulator of CYP2B induction. In this study, we investigated the effect of HDAC inhibitors on CAR-mediated CYP2B induction. The expression of CYP2B6 mRNA was induced in HepG2 cells stably expressing mouse CAR (Ym17) by HDAC inhibitors including valproic acid, phenylbutyrate, and trichostatin A. HDAC inhibitors activated the phenobarbital-responsive enhancer module of the CYP2B6 promoter in transient transfection reporter assays with Ym17 cells. Furthermore, HDAC inhibitors synergistically augmented the effect of the CAR ligand, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, in the transactivation of CYP2B6 mRNA and the promoter assay in Ym17 cells. Intraperitoneal injection of HDAC inhibitors induced Cyp2b10 mRNA in wild-type mice. However, such induction was not observed in CAR(−/−) mice. Immunoprecipitation demonstrated that CAR formed a complex with HDACs. HDAC inhibitors diminished the binding between CAR and HDAC1 and augmented the binding of steroid receptor coactivator-1 (SRC-1) to CAR. Furthermore, small interfering RNA knockdown of HDAC1 increased CYP2B6 mRNA expression. These results provide novel insight into the mechanism by which HDAC inhibitors affect gene expression of CYP2B6. HDAC inhibitors have the potential to up-regulate CYP2B6 through the dissociation of HDAC1 and recruitment of SRC-1 to receptor CAR.

Footnotes

  • This work was supported in part by the Ministry of Education, Science, Sports and Culture of the Japanese Government [Grant-in Aid for Scientific Research 18590716].

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.110.032854.

  • ABBREVIATIONS:

    VPA
    valproic acid
    CAR
    constitutive androstane receptor
    PB
    phenobarbital
    RXR
    retinoid X receptor
    UGT
    UDP glucuronosyltransferase
    TCPOBOP
    1,4 bis[2-(3,5-dichloropyridyloxy)]benzene
    PBREM
    phenobarbital-responsive enhancer module
    DR
    direct repeat
    NR
    nuclear receptor
    HDAC
    histone deacetylase
    SRC-1
    steroid receptor coactivator-1
    PBA
    phenylbutyrate
    TSA
    trichostatin A
    tk
    thymidine kinase
    PCR
    polymerase chain reaction
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    RT
    reverse transcription
    ChIP
    chromatin immunoprecipitation
    bp
    base pair
    gtPBREM
    phenobarbital-responsive enhancer module of UGT1A1.

  • Received February 16, 2010.
  • Accepted June 1, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (9)
Drug Metabolism and Disposition
Vol. 38, Issue 9
1 Sep 2010
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Research ArticleArticle

Histone Deacetylase Inhibitors Induce Cytochrome P450 2B by Activating Nuclear Receptor Constitutive Androstane Receptor

Daichi Takizawa, Satoru Kakizaki, Norio Horiguchi, Hiroki Tojima, Yuichi Yamazaki, Takeshi Ichikawa, Ken Sato and Masatomo Mori
Drug Metabolism and Disposition September 1, 2010, 38 (9) 1493-1498; DOI: https://doi.org/10.1124/dmd.110.032854

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Research ArticleArticle

Histone Deacetylase Inhibitors Induce Cytochrome P450 2B by Activating Nuclear Receptor Constitutive Androstane Receptor

Daichi Takizawa, Satoru Kakizaki, Norio Horiguchi, Hiroki Tojima, Yuichi Yamazaki, Takeshi Ichikawa, Ken Sato and Masatomo Mori
Drug Metabolism and Disposition September 1, 2010, 38 (9) 1493-1498; DOI: https://doi.org/10.1124/dmd.110.032854
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