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

A Cytochrome P450-Derived Epoxygenated Metabolite of Anandamide Is a Potent Cannabinoid Receptor 2-Selective Agonist

Natasha T. Snider, James A. Nast, Laura A. Tesmer and Paul F. Hollenberg
Molecular Pharmacology April 2009, 75 (4) 965-972; DOI: https://doi.org/10.1124/mol.108.053439
Natasha T. Snider
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
James A. Nast
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Laura A. Tesmer
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Paul F. Hollenberg
  • 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

Oxidation of the endocannabinoid anandamide by cytochrome P450 (P450) enzymes has the potential to affect signaling pathways within the endocannabinoid system and pharmacological responses to novel drug candidates targeting this system. We previously reported that the human cytochromes P450 2D6, 3A4, and 4F2 are high-affinity, high-turnover anandamide oxygenases in vitro, forming the novel metabolites hydroxyeicosatetraenoic acid ethanolamides and epoxyeicosatrienoic acid ethanolamides. The objective of this study was to investigate the possible biological significance of these metabolic pathways. We report that the 5,6-epoxide of anandamide, 5,6-epoxyeicosatrienoic acid ethanolamide (5,6-EET-EA), is a potent and selective cannabinoid receptor 2 (CB2) agonist. The Ki values for the binding of 5,6-EET-EA to membranes from Chinese hamster ovary (CHO) cells expressing either recombinant human CB1 or CB2 receptor were 11.4 μM and 8.9 nM, respectively. In addition, 5,6-EET-EA inhibited the forskolin-stimulated accumulation of cAMP in CHO cells stably expressing the CB2 receptor (IC50 = 9.8 ± 1.3 nM). Within the central nervous system, the CB2 receptor is expressed on activated microglia and is a potential therapeutic target for neuroinflammation. BV-2 microglial cells stimulated with low doses of interferon-γ exhibited an increased capacity for converting anandamide to 5,6-EET-EA, which correlated with increased protein expression of microglial P450 4F and 3A isoforms. Finally, we demonstrate that 5,6-EET-EA is more stable than anandamide in mouse brain homogenates and is primarily metabolized by epoxide hydrolase. Combined, our results suggest that epoxidation of anandamide by P450s to form 5,6-EET-EA represents an endocannabinoid bioactivation pathway in the context of immune cell function.

Footnotes

  • This work was supported in part by the National Institutes of Health National Cancer Institute [Grant CA16954]; the National Institutes of Health National Institute of General Medical Sciences [Grant T32-GM007767]; a predoctoral fellowship support from Merck and Co., Inc.; and a Howard Hughes Medical Institute through an Undergraduate Science Education Program to Kalamazoo College [Award 52005128].

  • ABBREVIATIONS: CNS, central nervous system; AM1241, (2-iodo-5-nitrophenyl)-[1-(1-methylpiperidin-2-ylmethyl)-1H-indol-3-yl]-methanone; AUDA, 2-(3-adamantan-1-yl-ureido)-dodecanoic acid; CB, cannabinoid receptor; CHO, Chinese hamster ovary; CP-55940, 5-(1,1-dimethylheptyl)-2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxy-propyl)-cyclohexyl]-phenol; DHET, dihydroxyeicosatrienoic acid; EA, ethanolamide; EET, epoxyeicosatrienoic acid; ESI-LC/MS, electrospray ionization-liquid chromatography/mass spectrometry; FAAH, fatty acid amide hydrolase; HETE, hydroxyeicosatetraenoic acid; IBMX, 3-isobutyl-1-methylxanthine; IFNγ, interferon γ; LPS, lipopolysaccharide; P450, cytochrome P450; WIN-55212-2, (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-napthalenylmethanone; TME, Tris/MgCl2/EDTA; TMEB, Tris/MgCl2/EDTA/bovine serum albumin; 5,6-EET-EA, 5,6-epoxyeicosatrienoic acid ethanolamide; 5,6-DHET-EA, 5,6-dihydroxyeicosatrienoic acid ethanolamide.

    • Received November 13, 2008.
    • Accepted January 26, 2009.
  • 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: 75 (4)
Molecular Pharmacology
Vol. 75, Issue 4
1 Apr 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 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.
A Cytochrome P450-Derived Epoxygenated Metabolite of Anandamide Is a Potent Cannabinoid Receptor 2-Selective Agonist
(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

A Cytochrome P450-Derived Epoxygenated Metabolite of Anandamide Is a Potent Cannabinoid Receptor 2-Selective Agonist

Natasha T. Snider, James A. Nast, Laura A. Tesmer and Paul F. Hollenberg
Molecular Pharmacology April 1, 2009, 75 (4) 965-972; DOI: https://doi.org/10.1124/mol.108.053439

Citation Manager Formats

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

Share
Research ArticleArticle

A Cytochrome P450-Derived Epoxygenated Metabolite of Anandamide Is a Potent Cannabinoid Receptor 2-Selective Agonist

Natasha T. Snider, James A. Nast, Laura A. Tesmer and Paul F. Hollenberg
Molecular Pharmacology April 1, 2009, 75 (4) 965-972; DOI: https://doi.org/10.1124/mol.108.053439
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

  • Mechanism of the selective action of paraherquamide A
  • Relapsed-Leukemia Model with NT5C2/PRPS1 Hotspot Mutations
  • The Binding Site for KCI807 in the Androgen Receptor
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