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Molecular Pharmacology

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Research ArticleArticle

Inhibition of Human UGT2B7 Gene Expression in Transgenic Mice by the Constitutive Androstane Receptor

M. F. Yueh, P. L. Mellon and R. H. Tukey
Molecular Pharmacology June 2011, 79 (6) 1053-1060; DOI: https://doi.org/10.1124/mol.110.070649
M. F. Yueh
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P. L. Mellon
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R. H. Tukey
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Abstract

The xenobiotic receptors, constitutive androstane receptor (CAR), and pregnane X receptor (PXR) regulate and alter the metabolism of xenobiotic substrates. Among the 19 functional UDP-glucuronosyltransferases (UGTs) in humans, UGT2B7 is involved in the metabolism of many structurally diverse xenobiotics and plays an important role in the clearance and detoxification of many therapeutic drugs. To examine whether this gene is regulated by CAR and PXR in vivo, transgenic mice expressing the entire UGT2B7 gene (TgUGT2B7) were created. Gene expression profiles revealed that UGT2B7 is differentially expressed in liver, kidney, adipocytes, brain, and estrogen-sensitive tissues, such as ovary and uterus. Liver UGT2B7 expression levels were decreased when TgUGT2B7 mice were treated with the CAR ligand 1,4-b-s-[2-(3,5,-dichloropyridyloxy)] (TCPOBOP) but not the PXR ligand pregnenolone 16α-carbonitrile. Although TCPOBOP decreased the levels of UGT2B7 mRNA in TgUGT2B7 mice, it had no affect on Tg(UGT2B7)Car(−/−) mice, adding support for a CAR-dependent mechanism contributing toward UGT2B7 gene suppression. Expression of promoter constructs in HepG2 cells showed the CAR-dependent inhibition was linked to hepatocyte nuclear factor-4α (HNF4α)-mediated transactivation of the UGT2B7 promoter. The inhibitory effect of CAR on UGT2B7 gene expression was validated in chromatin immunoprecipitation assays in which TCPOBOP treatment blocked HNF4α binding to the UGT2B7 promoter. These results suggest that HNF4α plays an important role in the constitutive expression of hepatic UGT2B7, and CAR acts as a negative regulator by interfering with HNF4α binding activity.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of Environmental Health Sciences [Grant P42-ES010337]; and the National Institutes of Health National Institute of General Medicine [Grant GM086713].

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

    doi:10.1124/mol.110.070649.

  • ABBREVIATIONS:

    UGT
    UDP-glucuronosyltransferase
    TCPOBOP
    1,4-b-s-[2-(3,5,-dichloropyridyloxy)]
    CAR
    constitute androstane receptors
    PXR
    pregnane X receptor
    HNF
    hepatocyte nuclear factor
    HDCA
    hyodeoxycholic acid
    XenR
    xenobiotic receptor
    CHIP
    chromatin immunoprecipitation
    FXR
    farnesoid X receptor
    kb
    kilobase(s)
    BAC
    bacterial artificial chromosome
    bp
    base pair(s)
    PCR
    polymerase chain reaction
    qPCR
    quantitative polymerase chain reaction
    DMSO
    dimethyl sulfoxide
    RT-PCR
    reverse-transcription polymerase chain reaction
    PCN
    pregnenolone-16α-carbonitrile
    Tg
    transgenic.

  • Received December 16, 2010.
  • Accepted March 17, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 79 (6)
Molecular Pharmacology
Vol. 79, Issue 6
1 Jun 2011
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Research ArticleArticle

Inhibition of Human UGT2B7 Gene Expression in Transgenic Mice by the Constitutive Androstane Receptor

M. F. Yueh, P. L. Mellon and R. H. Tukey
Molecular Pharmacology June 1, 2011, 79 (6) 1053-1060; DOI: https://doi.org/10.1124/mol.110.070649

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Research ArticleArticle

Inhibition of Human UGT2B7 Gene Expression in Transgenic Mice by the Constitutive Androstane Receptor

M. F. Yueh, P. L. Mellon and R. H. Tukey
Molecular Pharmacology June 1, 2011, 79 (6) 1053-1060; DOI: https://doi.org/10.1124/mol.110.070649
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