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

Metabolism of Tamoxifen by Recombinant Human Cytochrome P450 Enzymes: Formation of the 4-Hydroxy, 4′-Hydroxy andN-Desmethyl Metabolites and Isomerization oftrans-4-Hydroxytamoxifen

H. Kim Crewe, Lisa M. Notley, Rebecca M. Wunsch, Martin S. Lennard and Elizabeth M. J. Gillam
Drug Metabolism and Disposition August 2002, 30 (8) 869-874; DOI: https://doi.org/10.1124/dmd.30.8.869
H. Kim Crewe
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lisa M. Notley
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Rebecca M. Wunsch
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Martin S. Lennard
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Elizabeth M. J. Gillam
  • 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 cytochrome P450 (P450)-mediated biotransformation of tamoxifen is important in determining both the clearance of the drug and its conversion to the active metabolite,trans-4-hydroxytamoxifen. Biotransformation by P450 forms expressed extrahepatically, such as in the breast and endometrium, may be particularly important in determining tissue-specific effects of tamoxifen. Moreover, tamoxifen may serve as a useful probe drug to examine the regioselectivity of different forms. Tamoxifen metabolism was investigated in vitro using recombinant human P450s. Forms CYP1A1, 1A2, 1B1, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, 3A4, 3A5, and 3A7 were coexpressed in Escherichia coli with recombinant human NADPH-cytochrome P450 reductase. Bacterial membranes were harvested and incubated with tamoxifen ortrans-4-hydroxytamoxifen under conditions supporting P450-mediated catalysis. CYP2D6 was the major catalyst of 4-hydroxylation at low tamoxifen concentrations (170 ± 20 pmol/40 min/0.2 nmol P450 using 18 μM tamoxifen), but CYP2B6 showed significant activity at high substrate concentrations (28.1 ± 0.8 and 3.1 ± 0.5 nmol/120 min/0.2 nmol P450 for CYP2D6 and CYP2B6, respectively, using 250 μM tamoxifen). These two forms also catalyzed 4′-hydroxylation (13.0 ± 1.9 and 1.4 ± 0.1 nmol/120 min/0.2 nmol P450, respectively, for CYP2B6 and CYP2D6 at 250 μM tamoxifen; 0.51 ± 0.08 pmol/40 min/0.2 nmol P450 for CYP2B6 at 18 μM tamoxifen). Tamoxifen N-demethylation was mediated by CYP2D6, 1A1, 1A2, and 3A4, at low substrate concentrations, with contributions by CYP1B1, 2C9, 2C19 and 3A5 at high concentrations. CYP1B1 was the principal catalyst of 4-hydroxytamoxifentrans-cis isomerization but CYP2B6 and CYP2C19 also contributed.

Footnotes

  • Funding for this study was provided by the Kathleen Cuningham Foundation for Breast Cancer Research and the Australian Cancer Fund.

  • Abbreviations used are::
    P450
    cytochrome P450 (heme-thiolate protein P450)
    HPLC
    high-performance liquid chromatography
    hNPR
    human NADPH-cytochrome P450 reductase
    • Received December 17, 2001.
    • Accepted April 18, 2002.
  • 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: 30 (8)
Drug Metabolism and Disposition
Vol. 30, Issue 8
1 Aug 2002
  • 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.
Metabolism of Tamoxifen by Recombinant Human Cytochrome P450 Enzymes: Formation of the 4-Hydroxy, 4′-Hydroxy andN-Desmethyl Metabolites and Isomerization oftrans-4-Hydroxytamoxifen
(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

Metabolism of Tamoxifen by Recombinant Human Cytochrome P450 Enzymes: Formation of the 4-Hydroxy, 4′-Hydroxy andN-Desmethyl Metabolites and Isomerization oftrans-4-Hydroxytamoxifen

H. Kim Crewe, Lisa M. Notley, Rebecca M. Wunsch, Martin S. Lennard and Elizabeth M. J. Gillam
Drug Metabolism and Disposition August 1, 2002, 30 (8) 869-874; DOI: https://doi.org/10.1124/dmd.30.8.869

Citation Manager Formats

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

Share
Research ArticleArticle

Metabolism of Tamoxifen by Recombinant Human Cytochrome P450 Enzymes: Formation of the 4-Hydroxy, 4′-Hydroxy andN-Desmethyl Metabolites and Isomerization oftrans-4-Hydroxytamoxifen

H. Kim Crewe, Lisa M. Notley, Rebecca M. Wunsch, Martin S. Lennard and Elizabeth M. J. Gillam
Drug Metabolism and Disposition August 1, 2002, 30 (8) 869-874; DOI: https://doi.org/10.1124/dmd.30.8.869
Reddit logo Twitter logo Facebook 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

  • Ontogeny of CPPGL
  • Expression of AKR and SDR Isoforms in the Human Intestine
  • Interaction of Human OATP1B1 with PDZK1
Show more Article

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 © 2023 by the American Society for Pharmacology and Experimental Therapeutics