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Arachidonic acid-metabolizing cytochrome P450 enzymes are targets of omega-3 fatty acids

Item Type:Article
Title:Arachidonic acid-metabolizing cytochrome P450 enzymes are targets of omega-3 fatty acids
Creators Name:Arnold, C. and Markovic, M. and Blossey, K. and Wallukat, G. and Fischer, R. and Dechend, R. and Konkel, A. and von Schacky, C. and Luft, F.C. and Mueller, D.N. and Rothe, M. and Schunck, W.H.
Abstract:Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) protect against cardiovascular disease by largely unknown mechanisms. We tested the hypothesis that EPA and DHA may compete with arachidonic acid (AA) for the conversion by cytochrome P450 (CYP) enzymes resulting in the formation of alternative, physiologically active, metabolites. Renal and hepatic microsomes, as well as various CYP-isoforms, displayed equal or elevated activities when metabolizing EPA or DHA instead of AA. CYP2C/2J-isoforms converting AA to epoxyeicosatrienoic acids (EETs) preferentially epoxidized the omega-3 double bond and thereby produced 17,18-epoxyeicosatetraenoic (17,18-EEQ) and 19,20-epoxydocosapentaenoic acid (19,20-EDP) from EPA and DHA. We found that these omega-3 epoxides are highly active as antiarrhythmic agents, suppressing Ca2+-induced increased rate of spontaneous beating of neonatal rat cardiomyocytes, at low nanomolar concentrations. CYP4A/4F-isoforms omega-hydroxylating AA were less regioselective towards EPA and DHA, catalyzing predominantly omega- and omega minus-1 hydroxylation. Rats given dietary EPA/DHA supplementation exhibited substantial replacement of AA by EPA and DHA in membrane phospholipids in plasma, heart, kidney, liver, lung, and pancreas, with less pronounced changes in brain. The changes in fatty acids were accompanied by concomitant changes in endogenous CYP metabolite profiles (e.g. altering the EET:EEQ:EDP ratio from 87:0:13 to 27:18:55 in the heart). These results demonstrate that CYP-enzymes efficiently convert EPA and DHA to novel epoxy- and hydroxy-metabolites that could mediate some of the beneficial cardiovascular effects of dietary omega-3 fatty acids.
Keywords:Arachidonic Acid, Cytochrome P450, Eicosanoids Biosynthesis, Eicosapentaenoic Acid (EPA), Epoxygenase Pathway, Docosahexaenoic Acid, Hydroxylase, Animals, Mice, Rats
Source:Journal of Biological Chemistry
ISSN:0021-9258
Publisher:American Society for Biochemistry and Molecular Biology (U.S.A.)
Volume:285
Number:43
Page Range:32720-32733
Date:22 October 2010
Official Publication:https://doi.org/10.1074/jbc.M110.118406
PubMed:View item in PubMed

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