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Research ArticleArticle

Anandamide Oxidation by Wild-Type and Polymorphically Expressed CYP2B6 and CYP2D6

Chitra Sridar, Natasha T. Snider and Paul F. Hollenberg
Drug Metabolism and Disposition May 2011, 39 (5) 782-788; DOI: https://doi.org/10.1124/dmd.110.036707
Chitra Sridar
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Natasha T. Snider
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Paul F. Hollenberg
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Abstract

Anandamide is an arachidonic acid-derived endogenous cannabinoid that regulates normal physiological functions and pathophysiological responses within the central nervous system and in the periphery. Several cytochrome P450 (P450) isoforms metabolize anandamide to form hydroxylated and epoxygenated products. Human CYP2B6 and CYP2D6, which are expressed heterogeneously throughout the brain, exhibit clinically significant polymorphisms and are regulated by external factors, such as alcohol and smoking. Oxidative metabolism of anandamide by these two P450s may have important functional consequences for endocannabinoid system signaling. In this study, we investigated the metabolism of anandamide by wild-type CYP2B6 (2B6.1) and CYP2D6 (2D6.1) and by their common polymorphic mutants 2B6.4, 2B6.6, 2B6.9, and 2D6.34. Major differences in anandamide metabolism by the two isoforms and their mutants were found in vitro with respect to the formation of 20-hydroxyeicosatetraenoic acid ethanolamide (20-HETE-EA) and 14,15-epoxyeicosatetraenoic acid ethanolamide (14,15-EET-EA). Pharmacological studies showed that both 20-HETE-EA and 14,15-EET-EA bind to the rat brain cannabinoid CB1 receptor with lower affinities relative to that of anandamide. In addition, both products are degraded more rapidly than anandamide in rat brain homogenates. Their degradation occurs via different mechanisms involving either fatty acid amide hydrolase (FAAH), the major anandamide-degrading enzyme, or epoxide hydrolase (EH). Thus, the current findings provide potential new insights into the actions of inhibitors FAAH and EH, which are being developed as novel therapeutic agents, as well as a better understanding of the interactions between the cytochrome P450 monooxygenases and the endocannabinoid system.

Footnotes

  • This work was supported in part by the National Institutes of Health National Cancer Institute [Grant CA16954] (to P.F.H.); the National Institutes of Health National Institute of General Medical Sciences [Grant T32-GM007767]; Merck and Co., Inc. (predoctoral fellowship support); and the Michigan Institute for Clinical and Health Research Postdoctoral Translational Scholars Program [Award UL1-RR024986] (to N.T.S.).

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

    doi:10.1124/dmd.110.036707.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    FAAH
    fatty acid amide hydrolase
    HETE
    hydroxyeicosatetraenoic acid
    HETE-EA
    hydroxyeicosatetraenoic acid ethanolamide
    P450
    cytochrome P450
    ESI
    electrospray ionization
    LC
    liquid chromatography
    MS
    mass spectrometry
    MS/MS
    tandem mass spectrometry
    PMSF
    phenylmethylsulfonyl fluoride
    EET
    epoxyeicosatrienoic acid
    EET-EA
    epoxyeicosatrienoic acid ethanolamide
    CP-55940
    (−)-cis-3-[2-hydroxy-4(1,1-dimethyl-heptyl)phenyl]-trans-4-(3-hydroxypropyl)
    WIN-55212-2
    R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2, 3-de]1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate
    DHET-EA
    dihydroxyeicosatrienoic acid ethanolamide.

  • Received October 11, 2010.
  • Accepted February 2, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (5)
Drug Metabolism and Disposition
Vol. 39, Issue 5
1 May 2011
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Research ArticleArticle

Anandamide Oxidation by Wild-Type and Polymorphically Expressed CYP2B6 and CYP2D6

Chitra Sridar, Natasha T. Snider and Paul F. Hollenberg
Drug Metabolism and Disposition May 1, 2011, 39 (5) 782-788; DOI: https://doi.org/10.1124/dmd.110.036707

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Research ArticleArticle

Anandamide Oxidation by Wild-Type and Polymorphically Expressed CYP2B6 and CYP2D6

Chitra Sridar, Natasha T. Snider and Paul F. Hollenberg
Drug Metabolism and Disposition May 1, 2011, 39 (5) 782-788; DOI: https://doi.org/10.1124/dmd.110.036707
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