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
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
  • 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

Characterization of Multidrug Resistance 1a/P-Glycoprotein Knockout Rats Generated by Zinc Finger Nucleases

Xiaoyan Chu, Zuo Zhang, Jocelyn Yabut, Sarah Horwitz, John Levorse, Xiang-qing Li, Lei Zhu, Harmony Lederman, Rachel Ortiga, John Strauss, Xiaofang Li, Karen A. Owens, Jasminka Dragovic, Thomas Vogt, Raymond Evers and Myung K. Shin
Molecular Pharmacology February 2012, 81 (2) 220-227; DOI: https://doi.org/10.1124/mol.111.074179
Xiaoyan Chu
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Zuo Zhang
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jocelyn Yabut
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sarah Horwitz
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
John Levorse
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Xiang-qing Li
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lei Zhu
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Harmony Lederman
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Rachel Ortiga
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
John Strauss
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Xiaofang Li
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Karen A. Owens
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jasminka Dragovic
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Thomas Vogt
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Raymond Evers
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Myung K. Shin
  • 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

The development of zinc finger nuclease (ZFN) technology has enabled the genetic engineering of the rat genome. The ability to manipulate the rat genome has great promise to augment the utility of rats for biological and pharmacological studies. A Wistar Hannover rat model lacking the multidrug resistance protein Mdr1a P-glycoprotein (P-gp) was generated using a rat Mdr1a-specific ZFN. Mdr1a was completely absent in tissues, including brain and small intestine, of the knockout rat. Pharmacokinetic studies with the Mdr1a P-gp substrates loperamide, indinavir, and talinolol indicated that Mdr1a was functionally inactive in the blood-brain barrier and intestine in Mdr1a(−/−) rats. To identify possible compensatory mechanisms in Mdr1a(−/−) rats, the expression levels of drug-metabolizing enzyme and transporter-related genes were compared in brain, liver, kidney, and intestine of male and female Mdr1a(−/−) and control rats. In general, alterations in gene expression of these genes in Mdr1a(−/−) rats seemed to be modest, with more changes in female than in male rats. Taken together, our studies demonstrate that the ZFN-generated Mdr1a(−/−) rat will be a valuable tool for central nervous system drug target validation and determining the role of P-gp in drug absorption and disposition.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

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

    http://dx.doi.org/10.1124/mol.111.074179.

  • ABBREVIATIONS:

    ZFN
    zinc finger nuclease
    NHEJ
    nonhomologous end-joining
    HR
    homologous recombination
    KO
    knockout
    P-gp
    P-glycoprotein
    MDR/Mdr.
    multidrug resistance
    CNS
    central nervous system
    PCR
    polymerase chain reaction
    LC
    liquid chromatography
    MS/MS
    tandem mass spectrometry
    RT
    reverse transcription
    q
    quantitative
    OATP
    organic anion-transporting polypeptide
    AUC
    area under the curve.

  • Received June 22, 2011.
  • Accepted November 2, 2011.
  • Copyright © 2012 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: 81 (2)
Molecular Pharmacology
Vol. 81, Issue 2
1 Feb 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 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.
Characterization of Multidrug Resistance 1a/P-Glycoprotein Knockout Rats Generated by Zinc Finger Nucleases
(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

Mdr1a Knockout Rat

Xiaoyan Chu, Zuo Zhang, Jocelyn Yabut, Sarah Horwitz, John Levorse, Xiang-qing Li, Lei Zhu, Harmony Lederman, Rachel Ortiga, John Strauss, Xiaofang Li, Karen A. Owens, Jasminka Dragovic, Thomas Vogt, Raymond Evers and Myung K. Shin
Molecular Pharmacology February 1, 2012, 81 (2) 220-227; DOI: https://doi.org/10.1124/mol.111.074179

Citation Manager Formats

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

Share
Research ArticleArticle

Mdr1a Knockout Rat

Xiaoyan Chu, Zuo Zhang, Jocelyn Yabut, Sarah Horwitz, John Levorse, Xiang-qing Li, Lei Zhu, Harmony Lederman, Rachel Ortiga, John Strauss, Xiaofang Li, Karen A. Owens, Jasminka Dragovic, Thomas Vogt, Raymond Evers and Myung K. Shin
Molecular Pharmacology February 1, 2012, 81 (2) 220-227; DOI: https://doi.org/10.1124/mol.111.074179
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
    • Authorship Contributions
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • The binding site for KCI807 in the androgen receptor
  • Fatty acid amide hydrolase in cisplatin nephrotoxicity
  • eCB Signaling System in hiPSC-Derived Neuronal Cultures
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