Patient-Oriented and Epidemiological Research
Dietary omega-3 fatty acids modulate the eicosanoid profile in man primarily via the CYP-epoxygenase pathway[S]

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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
lipidomics
nutrition

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This work was supported by a grant from the Deutsche Forschungsgemeinschaft (DFG): Schu822/5; FOR 1054. The authors do not have any financial conflicts of interest to disclose.

    Abbreviations:

    AA

    arachidonic acid

    BK

    Ca2+ -activated potassium channel

    COX

    cyclooxygenase

    CYP

    cytochrome P450

    DHDP

    dihydroxydocosapentaenoic acid

    DHEQ

    dihydroxyeicosatetraenoic acid

    DHET

    dihydroxyeicosatrienoic acid

    EDP

    epoxydocosapentaenoic acid

    EEQ

    epoxyeicosatetraenoic acid

    EET

    epoxyeicosatrienoic acid

    HDHA

    hydroxydocosahexaenoic acid

    HEPE

    hydroxyeicosapentaenoic acid

    LOX

    lipoxygenase

    LT

    leukotriene

    PGE

    prostaglandin E

    PGI

    prostacyclin

    RBC

    red blood cell

    sEH

    soluble epoxide hydrolase

    SPE

    solid phase extraction

    TX

    thromboxane

[S]

The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of four tables.

1

R. Fischer and A. Konkel contributed equally to this work.