Fischer Robert, Konkel Anne, Mehling Heidrun, Blossey Katrin, Gapelyuk Andrej, Wessel Niels, von Schacky Clemens, Dechend Ralf, Muller Dominik N, Rothe Michael, Luft Friedrich C, Weylandt Karsten, Schunck Wolf-Hagen
Max Delbrueck Center for Molecular Medicine, Berlin, Germany Experimental and Clinical Research Center (ECRC), Berlin, Germany.
Max Delbrueck Center for Molecular Medicine, Berlin, Germany.
J Lipid Res. 2014 Jun;55(6):1150-64. doi: 10.1194/jlr.M047357. Epub 2014 Mar 16.
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.
细胞色素P450（CYP）依赖的花生四烯酸（AA）代谢产物有助于心血管功能的调节。CYP酶也可作用于二十碳五烯酸（EPA）和二十二碳六烯酸（DHA），生成更强效的血管舒张和潜在抗心律失常代谢产物，这表明膳食中的ω-3脂肪酸可有利地改变内源性CYP-类花生酸谱。为验证这一假设，对20名健康志愿者给予EPA/DHA补充剂，并分析环氧化酶、脂氧合酶（LOX）和CYP依赖途径产生的AA、EPA和DHA衍生代谢产物在循环和尿液水平的伴随变化。将ω-3指数从约4提高到8主要导致EPA衍生的CYP依赖环氧代谢产物大幅增加，随后是EPA和DHA衍生的LOX依赖单羟基代谢产物增加，包括消退素E和D家族的前体；未检测到消退素本身。代谢产物/前体脂肪酸比率表明，CYP环氧酶代谢EPA的效率比AA高8.6倍，代谢DHA的效率比AA高2.2倍。对白三烯、前列腺素E、前列环素和血栓素形成的影响仍然较弱。我们认为，EPA和DHA的CYP依赖环氧代谢产物可能是ω-3脂肪酸血管舒张和心脏保护作用的介质，可作为临床研究中调查EPA/DHA补充剂心血管效应的生物标志物。
