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
OtherShort Communication

CYTOCHROME P450 2C8 (CYP2C8)-MEDIATED HYDROXYLATION OF AN ENDOTHELIN ETA RECEPTOR ANTAGONIST IN HUMAN LIVER MICROSOMES

Bennett Ma, Raju Subramanian, Michael L. Schrag, A. David Rodrigues and Cuyue Tang
Drug Metabolism and Disposition May 2004, 32 (5) 473-478; DOI: https://doi.org/10.1124/dmd.32.5.473
Bennett Ma
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Raju Subramanian
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michael L. Schrag
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
A. David Rodrigues
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Cuyue Tang
  • 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

In vitro studies were performed to identify the human cytochrome P450 enzyme(s) involved in the hydroxylation (isopropyl moiety) of a previously reported endothelin ETA receptor antagonist, compound A [(+)-(5S,6R,7R)-2-isopropylamino-7-{4-methoxy-2-[(2R)-3-methoxy-2-methylpropyl]}-5-(3,4-methylenedioxyphenyl)cyclopenteno(1,2-b) pyridine 6-carboxylic acid]. Several lines of evidence indicated that the reaction was mainly catalyzed by CYP2C8. Of the 10 recombinant cytochrome P450 isoforms tested, only CYP2C8 exhibited hydroxylase activity. In agreement, inhibitory antibodies selective for CYP2C8 attenuated (>95%) the hydroxylase activity in human liver microsomes, whereas antibodies and chemical inhibitors selective for other cytochrome P450 isoforms had a minor or no effect on the reaction. In addition, the formation of the hydroxy metabolite correlated well with CYP2C8-selective paclitaxel 6α-hydroxylation (r2 ∼0.92; p < 0.0001) and amodiaquine N-de-ethylation (r2 ∼0.91; p < 0.0001) in a bank of human liver microsomes (n = 15 organ donors). Finally, compound A hydroxylase activity conformed to Michaelis-Menten kinetics, and the Km (Michaelis constant) in human liver microsomes was similar to that of CYP2C8 (∼10 μM). It is concluded that the hydroxylation of compound A is mainly catalyzed by CYP2C8, and thus the reaction can possibly serve as an alternative marker assay for CYP2C8 in human liver microsomes.

Footnotes

  • ↵1 Abbreviations used are: P450, cytochrome P450; LC-MS, liquid chromatography/mass spectrometry; Compound A, (+)-(5S,6R,7R)-2-isopropylamino-7-{4-methoxy-2-[(2R)-3-methoxy-2-methylpropyl]-5-(3,4-methylenedioxyphenyl)cyclopenteno(1,2-b) pyridine 6-carboxylic acid.

    • Received January 9, 2004.
    • Accepted February 13, 2004.
  • 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: 32 (5)
Drug Metabolism and Disposition
Vol. 32, Issue 5
1 May 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 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.
CYTOCHROME P450 2C8 (CYP2C8)-MEDIATED HYDROXYLATION OF AN ENDOTHELIN ETA RECEPTOR ANTAGONIST IN HUMAN LIVER MICROSOMES
(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
OtherShort Communication

CYTOCHROME P450 2C8 (CYP2C8)-MEDIATED HYDROXYLATION OF AN ENDOTHELIN ETA RECEPTOR ANTAGONIST IN HUMAN LIVER MICROSOMES

Bennett Ma, Raju Subramanian, Michael L. Schrag, A. David Rodrigues and Cuyue Tang
Drug Metabolism and Disposition May 1, 2004, 32 (5) 473-478; DOI: https://doi.org/10.1124/dmd.32.5.473

Citation Manager Formats

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

Share
OtherShort Communication

CYTOCHROME P450 2C8 (CYP2C8)-MEDIATED HYDROXYLATION OF AN ENDOTHELIN ETA RECEPTOR ANTAGONIST IN HUMAN LIVER MICROSOMES

Bennett Ma, Raju Subramanian, Michael L. Schrag, A. David Rodrigues and Cuyue Tang
Drug Metabolism and Disposition May 1, 2004, 32 (5) 473-478; DOI: https://doi.org/10.1124/dmd.32.5.473
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 and Discussion
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Preincubation Effects on Inhibition of OCT1 by CsA
  • Carbamazepine Metabolite and Hypersensitivity Reactions
  • SULT4A1 Preserves Mitochondrial Function
Show more Short Communications

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