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
  • My Cart

Search

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

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 jpet on Facebook
  • Follow jpet on Twitter
  • Follow jpet on LinkedIn
Research ArticleCELLULAR AND MOLECULAR

Role of Multidrug Resistance Protein 2 (MRP2, ABCC2) in Alkylating Agent Detoxification: MRP2 Potentiates Glutathione S-Transferase A1-1-Mediated Resistance to Chlorambucil Cytotoxicity

Pamela K. Smitherman, Alan J. Townsend, Timothy E. Kute and Charles S. Morrow
Journal of Pharmacology and Experimental Therapeutics January 2004, 308 (1) 260-267; DOI: https://doi.org/10.1124/jpet.103.057729
Pamela K. Smitherman
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alan J. Townsend
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Timothy E. Kute
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Charles S. Morrow
  • 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

Our previous studies have shown that the glutathione S-transferases (GSTs) can operate in synergy with the efflux transporter multidrug resistance protein 1 (MRP1, ABCC1) to confer resistance to the cyto- and genotoxicities of some anticancer drugs and carcinogens. The current study was designed to determine whether the alternative efflux transporter, MRP2 (ABCC2), can also potentiate GST-mediated detoxifications in HepG2 cells. HepG2 cells, which express high-level MRP2 but not MRP1, were stably transduced with GST expression vectors under tetracycline-repressible transcriptional control. MRP2 was able to support GSTA1-1-mediated resistance to chlorambucil (CHB) cytotoxicity in HepG2 cells. Resistance was GST isozyme-specific in that GSTP1a-1a and GSTM1a-1a failed to confer protection from CHB toxicity. Moreover, inhibition of MRP2 with sulfinpyrazone completely reversed GSTA1-1-associated resistance, indicating that MRP2-efflux function is required to potentiate GSTA1-1-mediated resistance. Relative transport by MRP1 versus MRP2 of monoglutathionyl-CHB (CHB-SG) was examined using inside-out plasma membrane vesicles derived from MCF7 cells transduced with MRP1 or MRP2 expression vectors. Both MRP1 and MRP2 transported CHB-SG efficiently, at the levels of protein expressed, with similar Vmax and with Km of 0.39 and 10 μM, respectively. We conclude that detoxification of CHB by GSTA1-1 requires the removal of the glutathione conjugate formed and that either MRP1 or MRP2 can serve this efflux function. These findings have implications for the role of MRP2 in detoxification of alkylating agents in the apical epithelium of liver and kidney where it is highly expressed as well as the role of MRP2 in the emergence of alkylating drug resistance in cancer cells.

Footnotes

  • This work was supported by National Institutes of Health Grant CA70338.

  • DOI: 10.1124/jpet.103.057729.

  • ABBREVIATIONS: GSH, glutathione; GST, glutathione S-transferase; CHB, chlorambucil; MRP, multidrug resistance protein; MRP1 and MRP2, multidrug resistance-associated protein, MRP isoform 1 (ABCC1), MRP isoform 2 (ABCC2); CHB-SG, monoglutathionyl-chlorambucil; bp, base pair(s); PBS, phosphate-buffered saline; BSA, bovine serum albumin.

    • Received July 28, 2003.
    • Accepted September 18, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
View Full Text

JPET 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

Journal of Pharmacology and Experimental Therapeutics: 308 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 308, Issue 1
1 Jan 2004
  • Table of Contents
  • About the Cover
  • Index by author
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Journal of Pharmacology and Experimental Therapeutics 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.
Role of Multidrug Resistance Protein 2 (MRP2, ABCC2) in Alkylating Agent Detoxification: MRP2 Potentiates Glutathione S-Transferase A1-1-Mediated Resistance to Chlorambucil Cytotoxicity
(Your Name) has forwarded a page to you from Journal of Pharmacology and Experimental Therapeutics
(Your Name) thought you would be interested in this article in Journal of Pharmacology and Experimental Therapeutics.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleCELLULAR AND MOLECULAR

Role of Multidrug Resistance Protein 2 (MRP2, ABCC2) in Alkylating Agent Detoxification: MRP2 Potentiates Glutathione S-Transferase A1-1-Mediated Resistance to Chlorambucil Cytotoxicity

Pamela K. Smitherman, Alan J. Townsend, Timothy E. Kute and Charles S. Morrow
Journal of Pharmacology and Experimental Therapeutics January 1, 2004, 308 (1) 260-267; DOI: https://doi.org/10.1124/jpet.103.057729

Citation Manager Formats

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

Share
Research ArticleCELLULAR AND MOLECULAR

Role of Multidrug Resistance Protein 2 (MRP2, ABCC2) in Alkylating Agent Detoxification: MRP2 Potentiates Glutathione S-Transferase A1-1-Mediated Resistance to Chlorambucil Cytotoxicity

Pamela K. Smitherman, Alan J. Townsend, Timothy E. Kute and Charles S. Morrow
Journal of Pharmacology and Experimental Therapeutics January 1, 2004, 308 (1) 260-267; DOI: https://doi.org/10.1124/jpet.103.057729
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
    • Materials and Methods
    • Results
    • Discussion
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • ML355 Effects on Platelets
  • H2S Activates Heme-Inhibited mitoBKCa Channels
  • Insulin Regulates Gene Expression of Midnolin
Show more Cellular and Molecular

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 JPET
  • 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
  • Molecular Pharmacology
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0103 (Online)

Copyright © 2022 by the American Society for Pharmacology and Experimental Therapeutics