Dietary omega-3 fatty acids modulate the eicosanoid profile in man primarily via the CYP-epoxygenase pathway

Abstract

Cytochrome P450 (CYP)-dependent metabolites of arachidonic acid (AA) contribute to the regulation of cardiovascular function. CYP enzymes also accept EPA and DHA to yield more potent vasodilatory and potentially anti-arrhythmic metabolites, suggesting that the endogenous CYP-eicosanoid profile can be favorably shifted by dietary omega-3 fatty acids. To test this hypothesis, 20 healthy volunteers were treated with an EPA/DHA supplement and analyzed for concomitant changes in the circulatory and urinary levels of AA-, EPA-, and DHA-derived metabolites produced by the cyclooxygenase-, lipoxygenase (LOX)-, and CYP-dependent pathways. Raising the Omega-3 Index from about four to eight primarily resulted in a large increase of EPA-derived CYP-dependent epoxy-metabolites followed by increases of EPA- and DHA-derived LOX-dependent monohydroxy-metabolites including the precursors of the resolvin E and D families; resolvins themselves were not detected. The metabolite/precursor fatty acid ratios indicated that CYP epoxygenases metabolized EPA with an 8.6-fold higher efficiency and DHA with a 2.2-fold higher efficiency than AA. Effects on leukotriene, prostaglandin E, prostacyclin, and thromboxane formation remained rather weak. We propose that CYP-dependent epoxy-metabolites of EPA and DHA may function as mediators of the vasodilatory and cardioprotective effects of omega-3 fatty acids and could serve as biomarkers in clinical studies investigating the cardiovascular effects of EPA/DHA supplementation. Cytochrome P450 (CYP)-dependent metabolites of arachidonic acid (AA) contribute to the regulation of cardiovascular function. CYP enzymes also accept EPA and DHA to yield more potent vasodilatory and potentially anti-arrhythmic metabolites, suggesting that the endogenous CYP-eicosanoid profile can be favorably shifted by dietary omega-3 fatty acids. To test this hypothesis, 20 healthy volunteers were treated with an EPA/DHA supplement and analyzed for concomitant changes in the circulatory and urinary levels of AA-, EPA-, and DHA-derived metabolites produced by the cyclooxygenase-, lipoxygenase (LOX)-, and CYP-dependent pathways. Raising the Omega-3 Index from about four to eight primarily resulted in a large increase of EPA-derived CYP-dependent epoxy-metabolites followed by increases of EPA- and DHA-derived LOX-dependent monohydroxy-metabolites including the precursors of the resolvin E and D families; resolvins themselves were not detected. The metabolite/precursor fatty acid ratios indicated that CYP epoxygenases metabolized EPA with an 8.6-fold higher efficiency and DHA with a 2.2-fold higher efficiency than AA. Effects on leukotriene, prostaglandin E, prostacyclin, and thromboxane formation remained rather weak. We propose that CYP-dependent epoxy-metabolites of EPA and DHA may function as mediators of the vasodilatory and cardioprotective effects of omega-3 fatty acids and could serve as biomarkers in clinical studies investigating the cardiovascular effects of EPA/DHA supplementation. Cytochrome P450 (CYP) enzymes catalyze the formation of biologically active epoxy- and hydroxy-metabolites of long-chain PUFAs (1Konkel A. Schunck W.H. Role of cytochrome P450 enzymes in the bioactivation of polyunsaturated fatty acids.Biochim. Biophys. Acta. 2011; 1814: 210-222Crossref PubMed Scopus (170) Google Scholar). Traditionally, and in line with the prevalence of n-6 PUFAs in the “Western diet”, arachidonic acid (AA) (20:4 n-6) has been considered as the main precursor and the corresponding metabolites were categorized as a subclass of eicosanoids (2Capdevila J.H. Falck J.R. Biochemical and molecular properties of the cytochrome P450 arachidonic acid monooxygenases.Prostaglandins Other Lipid Mediat. 2002; 68–69: 325-344Crossref PubMed Scopus (96) Google Scholar). CYP-eicosanoid formation is also known as the “third branch of the AA cascade,” complementary to the previously discovered cyclooxygenase (COX)- and lipoxygenase (LOX)-initiated pathways of prostanoid and leukotriene formation (3Funk C.D. Prostaglandins and leukotrienes: advances in eicosanoid biology.Science. 2001; 294: 1871-1875Crossref PubMed Scopus (3041) Google Scholar, 4Buczynski M.W. Dumlao D.S. Dennis E.A. Proteomics. An integrated omics analysis of eicosanoid biology.J. Lipid Res. 2009; 50: 1015-1038Abstract Full Text Full Text PDF PubMed Scopus (402) Google Scholar). Physiologically important AA-derived CYP-eicosanoids include a set of regio- and stereoisomeric epoxyeicosatrienoic acids (EETs) and 20-HETE (2Capdevila J.H. Falck J.R. 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A. metabolites of acid and 2013; PubMed Scopus Google Scholar). that CYP metabolites may serve as mediators in a of the effects to as cardiovascular cardiac and development omega-3 fatty and cardiovascular 2002; PubMed Scopus Google Scholar, Omega-3 polyunsaturated fatty acids and cardiovascular 2009; PubMed Scopus Google Scholar). on the of CYP that the profile of active CYP-eicosanoids is in by the dietary We this in a from to EPA- and DHA-derived epoxy- and in and dietary EPA/DHA K. A. cytochrome P450 enzymes are of omega-3 fatty 2010; Full Text Full Text PDF PubMed Scopus Google Scholar). 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The EPA-derived about from to and to in the not by EPA/DHA supplementation. monohydroxy-metabolites of EPA and DHA and from to and to the the EPA/DHA supplement The with the were also for the and for the with not the The that from from and from DHA to EPA/DHA with increases in and formation the with the a formation and the precursor formation of the EPA and of the DHA were the of the of the to EPA/DHA precursor of the resolvin also EPA/DHA of EPA/DHA on levels of were are as for for analysis and changes are indicated and To the effects of EPA/DHA on leukotriene and prostanoid the of metabolites by blood from the with the in the of blood to and from EPA EPA/DHA and to in the the AA-derived and remained of the The and and with the the formation of and with the the formation of that of and about EPA/DHA supplementation. thromboxane formation by EPA/DHA in of the and the AA-derived thromboxane and EPA-derived remained about in and of the this to and to the of and as as the corresponding were the of of and 20 for the and and for and of in to EPA/DHA the the and large and not with the not the formation of and also the levels of and the of and were and with the levels of metabolites and The formation of and followed the of precursor fatty acids DHA not metabolized the as indicated by the levels of and metabolites of AA and as as with and The with the of EPA and a the and the ratios to effects on formation the and not the of metabolites and also not increase the levels of not and metabolites produced by of AA and were also in the levels EPA/DHA and to in the The and and with the of the and levels were not that metabolites primarily in an The formation of not in as as and remained the of the EPA/DHA a in levels from an of to of the the levels to The effects with the levels levels were in in with of about in levels The blood pressure from to and of EPA/DHA to in blood pressure followed a not The blood pressure large and to be in blood pressure The of the that the CYP-eicosanoid is to changes in the dietary of the omega-3 fatty EPA and EPA/DHA a increase in the circulatory and urinary levels of EPA- and DHA-derived in are in line with the of in studies on enzymes that CYP accept EPA and DHA as (1Konkel A. 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