Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • For Subscribers
    • For Advertisers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in

Search

  • Advanced search
Drug Metabolism & Disposition
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
Drug Metabolism & Disposition

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • For Subscribers
    • For Advertisers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Visit dmd on Facebook
  • Follow dmd on Twitter
  • Follow ASPET on LinkedIn
Research ArticleArticle

Selective Agonism of Human Pregnane X Receptor by Individual Ginkgolides

Aik Jiang Lau, Guixiang Yang, Chun Wei Yap and Thomas K. H. Chang
Drug Metabolism and Disposition June 2012, 40 (6) 1113-1121; DOI: https://doi.org/10.1124/dmd.112.045013
Aik Jiang Lau
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Guixiang Yang
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Chun Wei Yap
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Thomas K. H. Chang
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF
Loading

Abstract

Ginkgolide A, ginkgolide B, ginkgolide C, and ginkgolide J are structurally related terpene trilactones present in Ginkgo biloba extract. Pregnane X receptor (PXR), glucocorticoid receptor (GR), and constitutive androstane receptor (CAR) regulate the expression of genes involved in diverse biological functions. In the present study, we investigated the effects of individual ginkgolides as single chemical entities on the function of human PXR (hPXR), human GR (hGR), and human CAR (hCAR). In cell-based reporter gene assays, none of the ginkgolides activated hGR or hCAR (wild-type and its SV23, SV24, and SV25 splice variants). Concentration-response experiments showed that ginkgolide A and ginkgolide B activated hPXR and rat PXR to a greater extent than ginkgolide C, whereas ginkgolide J had no effect. As determined by a time-resolved fluorescence resonance energy transfer competitive binding assay, ginkgolide A and ginkgolide B, but not ginkgolide C or ginkgolide J, were shown to bind to the ligand-binding domain of hPXR, consistent with molecular docking data. Compared with tetraethyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)ethenyl-1,1-bisphosphonate (SR12813) (a known agonist of hPXR), ginkgolide A and ginkgolide B were considerably less potent in binding to hPXR. These two ginkgolides recruited steroid receptor coactivator-1 to hPXR and increased hPXR target gene (CYP3A4) expression, as assessed by a mammalian two-hybrid assay and real-time polymerase chain reaction, respectively. In conclusion, the individual ginkgolides regulate the function of nuclear receptors in a receptor-selective and chemical-dependent manner. This study identifies ginkgolide A and ginkgolide B as naturally occurring agonists of hPXR and provides mechanistic insight into the structure-activity relationship in ligand activation of hPXR.

Footnotes

  • This research was supported by the Canadian Institutes of Health Research [Grant MOP-84581]; Singapore Ministry of Education Academic Research Fund Tier 1 [R-148-000-136-112]; and the Dawson Endowment Fund in Pharmaceutical Sciences at the University of British Columbia. 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://dmd.aspetjournals.org.

    http://dx.doi.org/10.1124/dmd.112.045013.

  • ABBREVIATIONS:

    PXR
    pregnane X receptor
    CAR
    constitutive androstane receptor
    GR
    glucocorticoid receptor
    hPXR
    human pregnane X receptor
    WT
    wild type
    SV
    splice variant
    hGR
    human glucocorticoid receptor
    hCAR
    human constitutive androstane receptor
    rPXR
    rat pregnane X receptor
    PCN
    pregnenolone 16α-carbonitrile
    DEHP
    di-(2-ethylhexyl)phthalate
    TCPOBOP
    1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene
    DMSO
    dimethyl sulfoxide
    CITCO
    6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime
    SR12813
    tetraethyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)ethenyl-1,1-bisphosphonate
    TR-FRET
    time-resolved fluorescence resonance energy transfer
    PCR
    polymerase chain reaction
    hHPRT
    human hypoxanthine phosphoribosyltransferase 1
    LDH
    lactate dehydrogenase
    MOE
    Molecular Operating Environment
    MM/GBVI
    molecular mechanics generalized born/volume integral
    SRC-1
    steroid receptor coactivator-1.

  • Received February 8, 2012.
  • Accepted March 2, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
View Full Text

Log in using your username and password

Forgot your user name or password?

Pay Per Article - You may access this article (from the computer you are currently using) for 1 day for US$35.00

Regain Access - You can regain access to a recent Pay per Article purchase if your access period has not yet expired.

PreviousNext
Back to top

In this issue

Drug Metabolism and Disposition: 40 (6)
Drug Metabolism and Disposition
Vol. 40, Issue 6
1 Jun 2012
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Editorial Board (PDF)
  • Front Matter (PDF)
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Drug Metabolism & Disposition article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Selective Agonism of Human Pregnane X Receptor by Individual Ginkgolides
(Your Name) has forwarded a page to you from Drug Metabolism & Disposition
(Your Name) thought you would be interested in this article in Drug Metabolism & Disposition.
Citation Tools
Research ArticleArticle

GINKGOLIDES, PXR, GR, AND CAR

Aik Jiang Lau, Guixiang Yang, Chun Wei Yap and Thomas K. H. Chang
Drug Metabolism and Disposition June 1, 2012, 40 (6) 1113-1121; DOI: https://doi.org/10.1124/dmd.112.045013

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Research ArticleArticle

GINKGOLIDES, PXR, GR, AND CAR

Aik Jiang Lau, Guixiang Yang, Chun Wei Yap and Thomas K. H. Chang
Drug Metabolism and Disposition June 1, 2012, 40 (6) 1113-1121; DOI: https://doi.org/10.1124/dmd.112.045013
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Authorship Contributions
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • NRF2-Independent Regulation of DMEs by Cadmium and ITCs
  • OATP Uptake in HEK293 Cells with and without Plasma
  • P450 Activities in Paired Liver and Small Intestinal Samples
Show more Articles

Similar Articles

  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Fast Forward by date
  • Fast Forward by section
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About DMD
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Journal of Pharmacology and Experimental Therapeutics
  • Molecular Pharmacology
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-009X (Online)

Copyright © 2019 by the American Society for Pharmacology and Experimental Therapeutics