QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.107.119321v1 321/2/590    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Snider, N. T. Articles by Hollenberg, P. F. Search for Related Content PubMed PubMed Citation Articles by Snider, N. T. Articles by Hollenberg, P. F.

METABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Anandamide Metabolism by Human Liver and Kidney Microsomal Cytochrome P450 Enzymes to Form Hydroxyeicosatetraenoic and Epoxyeicosatrienoic Acid Ethanolamides

Department of Pharmacology, University of Michigan, Ann Arbor, Michigan (N.T.S., U.M.K., P.F.H.); Cayman Chemical, Ann Arbor, Michigan (A.M.K.); and Institute of Bioorganic Chemistry and Petrochemistry, Kiev, Ukraine (A.M.K.)

The endocannabinoid anandamide is an arachidonic acid derivative that is found in most tissues where it acts as an important signaling mediator in neurological, immune, cardiovascular, and other functions. Cytochromes P450 (P450s) are known to oxidize arachidonic acid to the physiologically active molecules hydroxyeicosatetraenoic acids (HETEs) and epoxyeicosatrienoic acids (EETs), which play important roles in blood pressure regulation and inflammation. To determine whether anandamide can also be oxidized by P450s, its metabolism by human liver and kidney microsomes was investigated. The kidney microsomes metabolized anandamide to a single mono-oxygenated product, which was identified as 20-HETE-ethanolamide (EA). Human liver microsomal incubations with anandamide also produced 20-HETE-EA in addition to 5,6-, 8,9-, 11–12, and 14,15-EET-EA. The EET-EAs produced by the liver microsomal P450s were converted to their corresponding dihydroxy derivatives by microsomal epoxide hydrolase. P450 4F2 was identified as the isoform that is most probably responsible for the formation of 20-HETE-EA in both human kidney and human liver, with an apparent K_m of 0.7 µM. The apparent K_m values of the human liver microsomes for the formation of the EET-EAs were between 4 and 5 µM, and P450 3A4 was identified as the primary P450 in the liver responsible for epoxidation of anandamide. The in vivo formation and biological relevance of the P450-derived HETE and EET ethanolamides remains to be determined.

This article has been cited by other articles:

				N. T. Snider, J. A. Nast, L. A. Tesmer, and P. F. Hollenberg A Cytochrome P450-Derived Epoxygenated Metabolite of Anandamide Is a Potent Cannabinoid Receptor 2-Selective Agonist Mol. Pharmacol., April 1, 2009; 75(4): 965 - 972. [Abstract] [Full Text] [PDF]

				A. A. Spector Arachidonic acid cytochrome P450 epoxygenase pathway J. Lipid Res., April 1, 2009; 50(Supplement): S52 - S56. [Abstract] [Full Text] [PDF]

				N. T. Snider, M. J. Sikora, C. Sridar, T. J. Feuerstein, J. M. Rae, and P. F. Hollenberg The Endocannabinoid Anandamide Is a Substrate for the Human Polymorphic Cytochrome P450 2D6 J. Pharmacol. Exp. Ther., November 1, 2008; 327(2): 538 - 545. [Abstract] [Full Text] [PDF]