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
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
  • My Cart
Drug Metabolism & Disposition

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 dmd on Facebook
  • Follow dmd on Twitter
  • Follow ASPET on LinkedIn
Research ArticleArticle

The Importance of Heterogeneous Nuclear Ribonucleoprotein K on Cytochrome P450 2D2 Gene Regulation: Its Binding Is Reduced in Dark Agouti Rats

Noriaki Sakai, Kentaro Q. Sakamoto, Shoichi Fujita and Mayumi Ishizuka
Drug Metabolism and Disposition August 2009, 37 (8) 1703-1710; DOI: https://doi.org/10.1124/dmd.109.027284
Noriaki Sakai
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kentaro Q. Sakamoto
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shoichi Fujita
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mayumi Ishizuka
  • 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

Cytochrome P450 (P450) 2D2 (CYP2D2) enzyme is known to metabolize the majority of typical substrates of the human CYP2D6 enzyme, which is the most extensively characterized polymorphic drug-metabolizing enzyme. Despite its impact on drug metabolism in rats, the transcriptional regulation of CYP2D2 remains to be elucidated. We clarified the molecular mechanism of CYP2D2 gene expression. The CYP2D2 gene was positively regulated by the poly(C)-binding protein heterogeneous nuclear ribonucleoprotein K (hnRNP K) through a transcriptional regulatory element located in the 5′-flanking region from –94 to –113. To date, nothing is known about the potential role of hnRNP K in P450 gene regulation. Thus, this is the first report that hnRNP K protein is involved in CYP2D2 gene regulation. Furthermore, we elucidated the genetic basis of the extremely low expression of CYP2D2 mRNA in Dark Agouti (DA) rats. Because of its relatively low abundance, DA rats have been frequently used for the study of CYP2D substrate metabolism as the animal model of the poor metabolizer phenotype for CYP2D6 compared with Sprague-Dawley rats as an extensive metabolizer phenotype. We found a single substitution within the transcriptional regulatory element of the CYP2D2 gene in DA rats. The mutation was detected in the polypyrimidine sequence that is the preferred binding site for hnRNP K protein. The mutation within the transcriptional regulatory element attenuated the binding of hnRNP K protein. In conclusion, decreased recruitment of hnRNP K protein to the mutated sequence causes the low expression of CYP2D2 mRNA in DA rats.

Footnotes

  • This work was supported in part by the Japanese Ministry of Education, Science, Sports, Culture, and Technology [Grants 19671001, 19208028]; and the Japan Society for the Promotion of Science [Grant 18.4513].

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

  • doi:10.1124/dmd.109.027284.

  • ABBREVIATIONS: P450, cytochrome P450; PM, poor metabolizer; EM, extensive metabolizer; DA, Dark Agouti; SD, Sprague-Dawley; MALDI-TOF, matrix-assisted laser desorption/ionization time-of-flight; hnRNP K, heterogeneous nuclear ribonucleoprotein K; SNP, single nucleotide polymorphism; Sp1, specificity protein 1; C/EBP, CCAAT/enhancer binding protein; GATA, GATA binding protein; STAT, signal transducers and activators of transcription; bp, base pair; PCR, polymerase chain reaction; EMSA, electrophoresis mobility shift assay; TFA, trifluoroacetic acid; ChIP, chromatin immunoprecipitation; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; kb, kilobase.

    • Accepted April 30, 2009.
    • Received February 23, 2009.
  • The American Society for Pharmacology and Experimental Therapeutics
View Full Text

 

DMD 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

Drug Metabolism and Disposition: 37 (8)
Drug Metabolism and Disposition
Vol. 37, Issue 8
1 Aug 2009
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Back Matter (PDF)
  • 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.
The Importance of Heterogeneous Nuclear Ribonucleoprotein K on Cytochrome P450 2D2 Gene Regulation: Its Binding Is Reduced in Dark Agouti Rats
(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.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleArticle

The Importance of Heterogeneous Nuclear Ribonucleoprotein K on Cytochrome P450 2D2 Gene Regulation: Its Binding Is Reduced in Dark Agouti Rats

Noriaki Sakai, Kentaro Q. Sakamoto, Shoichi Fujita and Mayumi Ishizuka
Drug Metabolism and Disposition August 1, 2009, 37 (8) 1703-1710; DOI: https://doi.org/10.1124/dmd.109.027284

Citation Manager Formats

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

Share
Research ArticleArticle

The Importance of Heterogeneous Nuclear Ribonucleoprotein K on Cytochrome P450 2D2 Gene Regulation: Its Binding Is Reduced in Dark Agouti Rats

Noriaki Sakai, Kentaro Q. Sakamoto, Shoichi Fujita and Mayumi Ishizuka
Drug Metabolism and Disposition August 1, 2009, 37 (8) 1703-1710; DOI: https://doi.org/10.1124/dmd.109.027284
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
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • P450 cell lines for xenobiotic metabolite generation
  • Human ADME properties of abrocitinib
  • Impact of physiological microenvironments on HepaRG cells
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 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 © 2022 by the American Society for Pharmacology and Experimental Therapeutics