Abstract 618: Dietary Omega-3 Fatty Acid Compete With Arachidonic Acid For The Formation Of Physiologically Active Cyp-eicosanoids In Man

Abstract

Cytochrome P450 (CYP)-dependent metabolites of arachidonic acid (AA; 20:4 n-6) regulate vascular, renal, and cardiac function. However, the same CYP isoforms that metabolize AA also accept eicosapentaenoic acid (EPA; 20:5 n-3) and docosahexaenoic acid (DHA; 22:6 n-3) as alternative substrates, suggesting that the profile of physiologically active CYP-eicosanoids can be modulated in vivo by changing the dietary fatty acid composition. After we proved this hypothesis in rodents, we now expanded our studies to humans. The trial included 10 healthy men and 10 women aged 18 to 45 years (EudraCT: 2009-013458-33). They ingested 1 Omacor® capsule (480 mg EPA + 360 mg DHA) daily for the first 4 weeks, and two capsules daily in the subsequent 4 weeks, followed by 8 weeks of wash-out. Fatty acids and CYP-dependent metabolites were determined in blood and urine samples by gas chromatography and LC-MS/MS, respectively. The Omega-3 Index (% EPA + DHA of total fatty acids in red blood cells) increased from 4.98±0.80 to 8.03±1.06 at week 8 (p <0.001 vs. week 0), and declined to 6.33±1.44 at week 16. Concomitantly, the plasma CYP-epoxyeicosanoid index, defined as the ratio of EPA- plus DHA- vs. AA-derived epoxymetabolites ((EEQs+EDPs)/EETs), increased almost 3-fold from 0.83±0.05 to 2.35±0.17 (p <0.001; week 0 vs. week 8), and declined to 1.58±0.53 at week 16. In urine, the corresponding hydrolysis products were detectable and their ratio increased from 1.57±1.19 to 4.74±2.61 after 2g Omacor ® , and returned to baseline (1.38±0.75) after cessation of supplementation. Among the individual regioisomeric epoxymetabolites, AA-derived 14,15-EET predominated at baseline but was clearly exceeded by the EPA-derived 17,18-EEQ after EPA/DHA supplementation (3.24±0.26 vs.1.88±0.22 at week 0 and 2.96±0.24 vs. 6.15±0.43 ng/ml plasma at week 8). The plasma level of DHA-derived 19,20-EDP increased from 1.23±0.11 at week 0 to 2.52±0.19 at week 8. These results demonstrate that the human CYP-eicosanoid profile is highly susceptible to changes in dietary fatty acids. In particular, EPA/DHA supplementation promotes the formation of 17,18-EEQ that we previously identified as a candidate for mediating vasodilatory and antiarrhythmic effects of omega-3 fatty acids.