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Research ArticleCellular and Molecular

Isoform-Selective Activation of Human Constitutive Androstane Receptor by Ginkgo biloba Extract: Functional Analysis of the SV23, SV24, and SV25 Splice Variants

Aik Jiang Lau, Guixiang Yang and Thomas K. H. Chang
Journal of Pharmacology and Experimental Therapeutics November 2011, 339 (2) 704-715; DOI: https://doi.org/10.1124/jpet.111.186130
Aik Jiang Lau
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Guixiang Yang
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Thomas K. H. Chang
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Abstract

Naturally occurring splice variants of human constitutive androstane receptor (hCAR) exist, including hCAR-SV23 (insertion of amino acids SPTV), hCAR-SV24 (APYLT), and hCAR-SV25 (SPTV and APYLT). An extract of Ginkgo biloba was reported to activate hCAR-SV24 and the wild type (hCAR-WT). However, it is not known whether it selectively affects hCAR splice variants, how it activates hCAR isoforms, and which chemical is responsible for the effects of the extract. Therefore, we evaluated the impact of G. biloba extract on the functionality of hCAR-SV23, hCAR-SV24, hCAR-SV25, and hCAR-WT and compared it with that of phenobarbital, di-(2-ethylhexyl)phthalate (DEHP), 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime (CITCO), and 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) in cell-based reporter gene assays. Among the hCAR splice variants investigated, only hCAR-SV23 was activated by G. biloba extract, and this required cotransfection of a retinoid X receptor α (RXRα) expression plasmid. The extract activated hCAR-SV23 to a lesser extent than hCAR-WT, but ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J, and bilobalide were not responsible for the effects of the extract. CITCO activated hCAR-SV23, hCAR-SV24, and hCAR-WT. By comparison, phenobarbital activated hCAR-WT, whereas DEHP activated hCAR-SV23, hCAR-SV24 (with exogenous RXRα supplementation), and hCAR-WT. TCPOBOP did not affect the activity of any of the isoforms. G. biloba extract and phenobarbital did not bind or recruit coactivators to the ligand-binding domains of hCAR-WT and hCAR-SV23, whereas positive results were obtained with the controls (CITCO for hCAR-WT and DEHP for hCAR-SV23). In conclusion, G. biloba extract activates hCAR in an isoform-selective manner, and hCAR-SV23, hCAR-SV24, and hCAR-WT have overlapping, but distinct, sets of ligands.

Footnotes

  • This research was supported by the Canadian Institutes of Health Research [Grant MOP-84581]. T.K.H.C. received a Senior Scholar Award from the Michael Smith Foundation for Health Research.

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

    doi:10.1124/jpet.111.186130.

  • ABBREVIATIONS:

    CAR
    constitutive androstane receptor
    hCAR
    human CAR
    mCAR
    mouse CAR
    CITCO
    6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime
    DEHP
    di-(2-ethylhexyl)phthalate
    DMSO
    dimethyl sulfoxide
    RXRα
    retinoid X receptor α
    hRXRα
    human RXRα
    hSRC
    human steroid receptor coactivator
    PK11195
    1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carboxamide
    TCPOBOP
    1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene
    WT
    wild type
    CAS
    Chemical Abstracts Service
    bp
    base pair(s)
    aa
    amino acids.

  • Received July 18, 2011.
  • Accepted August 22, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 339 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 339, Issue 2
1 Nov 2011
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Research ArticleCellular and Molecular

G. biloba and hCAR Splice Variants

Aik Jiang Lau, Guixiang Yang and Thomas K. H. Chang
Journal of Pharmacology and Experimental Therapeutics November 1, 2011, 339 (2) 704-715; DOI: https://doi.org/10.1124/jpet.111.186130

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Research ArticleCellular and Molecular

G. biloba and hCAR Splice Variants

Aik Jiang Lau, Guixiang Yang and Thomas K. H. Chang
Journal of Pharmacology and Experimental Therapeutics November 1, 2011, 339 (2) 704-715; DOI: https://doi.org/10.1124/jpet.111.186130
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