Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • 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
  • 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
    • 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
  • Visit dmd on Facebook
  • Follow dmd on Twitter
  • Follow ASPET on LinkedIn
Research ArticleArticle

Expression of the Human UGT1 Locus in Transgenic Mice by 4-Chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic Acid (WY-14643) and Implications on Drug Metabolism through Peroxisome Proliferator-Activated Receptor α Activation

Kathy Senekeo-Effenberger, Shujuan Chen, Erin Brace-Sinnokrak, Jessica A. Bonzo, Mei-Fei Yueh, Upendra Argikar, Jenny Kaeding, Jocelyn Trottier, Rory P. Remmel, Joseph K. Ritter, Olivier Barbier and Robert H. Tukey
Drug Metabolism and Disposition March 2007, 35 (3) 419-427; DOI: https://doi.org/10.1124/dmd.106.013243
Kathy Senekeo-Effenberger
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shujuan Chen
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Erin Brace-Sinnokrak
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jessica A. Bonzo
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mei-Fei Yueh
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Upendra Argikar
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jenny Kaeding
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jocelyn Trottier
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Rory P. Remmel
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Joseph K. Ritter
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Olivier Barbier
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Robert H. Tukey
  • 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

The UDP-glucuronosyltransferase (UGT) 1A genes in humans have been shown to be differentially regulated in a tissue-specific fashion. Transgenic mice carrying the human UGT1 locus (Tg-UGT1) were recently created, demonstrating that expression of the nine UGT1A genes closely resembles the patterns of expression observed in human tissues. In the present study, UGT1A1, UGT1A3, UGT1A4, and UGT1A6 have been identified as targets of the peroxisome proliferator-activated receptor (PPAR) α in human hepatocytes and Tg-UGT1 mice. Oral administration of the PPARα agonist 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (pirinixic acid, WY-14643) to Tg-UGT1 mice led to induction of these proteins in either the liver, gastrointestinal tract, or kidney. The levels of induced UGT1A3 gene transcripts in liver and UGT1A4 protein in small intestine correlated with induced lamotrigine glucuronidation activity in these tissues. With UGT1A3 previously identified as the major human enzyme involved in human C24-glucuronidation of lithocholic acid (LCA), the dramatic induction of liver UGT1A3 RNA in Tg-UGT1 mice was consistent with the formation of LCA-24G in plasma. Furthermore, PPAR-responsive elements (PPREs) were identified flanking the UGT1A1, UGT1A3, and UGT1A6 genes by a combination of site-directed mutagenesis, specific binding to PPARα and retinoic acid X receptor α, and functional response of the concatenated PPREs in HepG2 cells overexpressing PPARα. In conclusion, these results suggest that oral fibrate treatment in humans will induce the UGT1A family of proteins in the gastrointestinal tract and liver, influencing bile acid glucuronidation and first-pass metabolism of other drugs that are taken concurrently with hypolipidemic therapy.

Footnotes

  • This work was funded by National Public Health Service Grants GM49135 and ES10337.

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

  • doi:10.1124/dmd.106.013243.

  • ABBREVIATIONS: UGT, UDP-glucuronosyltransferase; Tg-UGT1, transgenic UGT1; PXR, pregnane X-receptor; Ah receptor, aryl hydrocarbon receptor; LXR, liver X receptor; PPAR, peroxisome proliferator-activated receptor; RXR, retinoic acid X receptor; WY-14643, 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid, pirinixic acid; DMSO, dimethyl sulfoxide; WT, wild-type; LCA, lithocholic acid; PCR, polymerase chain reaction; RT, reverse transcription; EMSA, electrophoretic mobility shift assay; DR1, direct repeat response element that is separated by 1 nucleotide; PPRE, PPAR-responsive element; SV40, Simian virus 40; BA, bile acid; PREM, phenobarbital-responsive enhancer module; CAR, constitutive androstane receptor; MOPS, 4-morpholinepropanesulfonic acid.

    • Received October 9, 2006.
    • Accepted December 5, 2006.
  • 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: 35 (3)
Drug Metabolism and Disposition
Vol. 35, Issue 3
1 Mar 2007
  • 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.
Expression of the Human UGT1 Locus in Transgenic Mice by 4-Chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic Acid (WY-14643) and Implications on Drug Metabolism through Peroxisome Proliferator-Activated Receptor α Activation
(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

Expression of the Human UGT1 Locus in Transgenic Mice by 4-Chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic Acid (WY-14643) and Implications on Drug Metabolism through Peroxisome Proliferator-Activated Receptor α Activation

Kathy Senekeo-Effenberger, Shujuan Chen, Erin Brace-Sinnokrak, Jessica A. Bonzo, Mei-Fei Yueh, Upendra Argikar, Jenny Kaeding, Jocelyn Trottier, Rory P. Remmel, Joseph K. Ritter, Olivier Barbier and Robert H. Tukey
Drug Metabolism and Disposition March 1, 2007, 35 (3) 419-427; DOI: https://doi.org/10.1124/dmd.106.013243

Citation Manager Formats

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

Expression of the Human UGT1 Locus in Transgenic Mice by 4-Chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic Acid (WY-14643) and Implications on Drug Metabolism through Peroxisome Proliferator-Activated Receptor α Activation

Kathy Senekeo-Effenberger, Shujuan Chen, Erin Brace-Sinnokrak, Jessica A. Bonzo, Mei-Fei Yueh, Upendra Argikar, Jenny Kaeding, Jocelyn Trottier, Rory P. Remmel, Joseph K. Ritter, Olivier Barbier and Robert H. Tukey
Drug Metabolism and Disposition March 1, 2007, 35 (3) 419-427; DOI: https://doi.org/10.1124/dmd.106.013243
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
    • Materials and Methods
    • Results
    • Discussion
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Humanized PXR-CAR-CYP3A4/7 Mouse as Model of Induction
  • Ozanimod Human Metabolism and Disposition
  • High-Throughput Characterization of SLCO1B1 VUS
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 © 2021 by the American Society for Pharmacology and Experimental Therapeutics