Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • 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
  • Log out
  • My Cart

Search

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

Advanced Search

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

Metformin Represses Drug-Induced Expression of CYP2B6 by Modulating the Constitutive Androstane Receptor Signaling

Hui Yang, Brandy Garzel, Scott Heyward, Timothy Moeller, Paul Shapiro and Hongbing Wang
Molecular Pharmacology February 2014, 85 (2) 249-260; DOI: https://doi.org/10.1124/mol.113.089763
Hui Yang
Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland (H.Y., B.G., P.S., H.W.); and Bioreclamation In Vitro Technologies (S.H., T.M.), Baltimore, Maryland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Brandy Garzel
Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland (H.Y., B.G., P.S., H.W.); and Bioreclamation In Vitro Technologies (S.H., T.M.), Baltimore, Maryland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Scott Heyward
Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland (H.Y., B.G., P.S., H.W.); and Bioreclamation In Vitro Technologies (S.H., T.M.), Baltimore, Maryland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Timothy Moeller
Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland (H.Y., B.G., P.S., H.W.); and Bioreclamation In Vitro Technologies (S.H., T.M.), Baltimore, Maryland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Paul Shapiro
Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland (H.Y., B.G., P.S., H.W.); and Bioreclamation In Vitro Technologies (S.H., T.M.), Baltimore, Maryland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hongbing Wang
Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland (H.Y., B.G., P.S., H.W.); and Bioreclamation In Vitro Technologies (S.H., T.M.), Baltimore, Maryland
  • 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 + SI
  • PDF
Loading

Abstract

Metformin is currently the most widely used drug for the treatment of type 2 diabetes. Mechanistically, metformin interacts with many protein kinases and transcription factors that alter the expression of numerous downstream target genes governing lipid metabolism, cell proliferation, and drug metabolism. The constitutive androstane receptor (CAR, NR1i3), a known xenobiotic sensor, has recently been recognized as a novel signaling molecule, in that its activation could be regulated by protein kinases in addition to the traditional ligand binding. We show that metformin could suppress drug-induced expression of CYP2B6 (a typical target gene of CAR) by modulating the phosphorylation status of CAR. In human hepatocytes, metformin robustly suppressed the expression of CYP2B6 induced by both indirect (phenobarbital) and direct CITCO [6-(4-chlorophenyl)imidazo[2,1-b]1,3thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime] activators of human CAR. Mechanistic investigation revealed that metformin specifically enhanced the phosphorylation of threonine-38 of CAR, which blocks CAR nuclear translocation and activation. Moreover, we showed that phosphorylation of CAR by metformin was primarily an AMP-activated protein kinase– and extracellular signal-regulated kinase 1/2–dependent event. Additional two-hybrid and coimmunoprecipitation assays demonstrated that metformin could also disrupt CITCO-mediated interaction between CAR and the steroid receptor coactivator 1 or the glucocorticoid receptor-interacting protein 1. Our results suggest that metformin is a potent repressor of drug-induced CYP2B6 expression through specific inhibition of human CAR activation. Thus, metformin may affect the metabolism and clearance of drugs that are CYP2B6 substrates.

Footnotes

    • Received September 18, 2013.
    • Accepted November 18, 2013.
  • This work was supported in part by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant R01 DK061652]; and the National Institutes of Health National Institute of General Medical Sciences [Grant R01 GM107058].

  • dx.doi.org/10.1124/mol.113.089763.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
View Full Text

MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years. 

Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page. 

 

  • Click here for information on institutional subscriptions.
  • Click here for information on individual ASPET membership.

 

Log in using your username and password

Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
PreviousNext
Back to top

In this issue

Molecular Pharmacology: 85 (2)
Molecular Pharmacology
Vol. 85, Issue 2
1 Feb 2014
  • 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 Molecular Pharmacology 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.
Metformin Represses Drug-Induced Expression of CYP2B6 by Modulating the Constitutive Androstane Receptor Signaling
(Your Name) has forwarded a page to you from Molecular Pharmacology
(Your Name) thought you would be interested in this article in Molecular Pharmacology.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleArticle

Metformin Suppresses CYP2B6 Induction by CAR Phosphorylation

Hui Yang, Brandy Garzel, Scott Heyward, Timothy Moeller, Paul Shapiro and Hongbing Wang
Molecular Pharmacology February 1, 2014, 85 (2) 249-260; DOI: https://doi.org/10.1124/mol.113.089763

Citation Manager Formats

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

Share
Research ArticleArticle

Metformin Suppresses CYP2B6 Induction by CAR Phosphorylation

Hui Yang, Brandy Garzel, Scott Heyward, Timothy Moeller, Paul Shapiro and Hongbing Wang
Molecular Pharmacology February 1, 2014, 85 (2) 249-260; DOI: https://doi.org/10.1124/mol.113.089763
del.icio.us logo Digg logo Reddit logo Twitter 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
    • Acknowledgments
    • Authorship Contributions
    • Footnotes
    • Abbreviations
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Fatty acid amide hydrolase in cisplatin nephrotoxicity
  • eCB Signaling System in hiPSC-Derived Neuronal Cultures
  • Benzbromarone relaxes airway smooth muscle via BK activation
Show more Articles

Similar Articles

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

ASPET's Other Journals

  • Drug Metabolism and Disposition
  • Journal of Pharmacology and Experimental Therapeutics
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0111 (Online)

Copyright © 2023 by the American Society for Pharmacology and Experimental Therapeutics