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

Abstract

This article is available online at http://www.jlr.org Cytochrome P450 (CYP) enzymes catalyze the formation of biologically active epoxy-and hydroxy-metabolites of long-chain PUFAs ( 1 ). 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 ( 2 ). 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 ( 3, 4 ).Physiologically important AA-derived CYP-eicosanoids include a set of regio-and stereoisomeric epoxyeicosatrienoic acids (EETs) and 20-HETE ( 2, 5 ). EETs and 20-HETE play partially opposing roles in the regulation of vascular, renal, and cardiac function ( 6-9 ). The contribution of EETs to cardiovascular function is infl uenced by the soluble epoxide hydrolase (sEH) that metabolizes EETs to less potent dihydroxyeicosatrienoic acids (DHETs) ( 10 ). Imbalances in CYP-eicosanoid formation are linked to the development of endothelial dysfunction and hypertension; ischemia-induced injury of the heart, kidney and brain; infl ammatory disorders; and atherosclerosis (11)(12)(13)(14)(15)(16)(17).Recent studies demonstrated that the same CYP isoforms that epoxidize or hydroxylate AA, also effi ciently metabolize

Dietary Omega-3 Polyunsaturated Fatty Acids Prevent Vascular Dysfunction and Attenuate Cytochrome P4501A1 Expression by 2,3,7,8-Tetrachlorodibenzo-P-Dioxin

“…We observed this in RBCs and this is consistent with results from human RBCs and various tissues in animal models in which diets are supplemented with n-3 PUFAs (Agbor et al, 2014;Arnold et al, 2010b;Fischer et al, 2014;Schebb et al, 2014). This shift in PUFA membrane composition subsequently shifts the P450-mediated omega-hydroxylase metabolic profile (Agbor et al, 2014;Arnold et al, 2010b;Fischer et al, 2014). Less of the vasoconstrictor, 20-HETE, is generated in the liver and more 20-HEPE and 22-HDHA are generated in liver and plasma, suggesting that the substrate for Cyp4a12 shifts away from AA and towards EPA and DHA.…”

“…First, the n-3 PUFA diet significantly decreases the percentage of AA and increases the percentage of EPA and DHA in cell membranes. We observed this in RBCs and this is consistent with results from human RBCs and various tissues in animal models in which diets are supplemented with n-3 PUFAs (Agbor et al, 2014;Arnold et al, 2010b;Fischer et al, 2014;Schebb et al, 2014). This shift in PUFA membrane composition subsequently shifts the P450-mediated omega-hydroxylase metabolic profile (Agbor et al, 2014;Arnold et al, 2010b;Fischer et al, 2014).…”

Specialized pro-resolving mediators: do they circulate in plasma?

“…Arachidonate metabolites derived from the CYPepoxygenase pathway are known to be bioactive, but little is known about the EPA-and DHA-derived epoxides or their diol products that result from epoxide hydrolysis. Interestingly, the majority of these EPA and DHA epoxides (90%) were found as esterifi ed products in plasma that were released upon base hydrolysis ( 7 ). The Penn group also found signifi cant elevation of the most abundant of these CYP-epoxygenase products identifi ed by the Berlin group as 17(18)-EpETE ( Fig.…”

CYP-13A12 of the nematode Caenorhabditis elegans is a PUFA-epoxygenase involved in behavioural response to reoxygenation

“…All data were calculated per minute and nmol of CYP protein, as determined by the corresponding COD. The metabolite profiles were also analysed by LC-MS/MS (liquid chromatographymass spectrometry) using a triple quadrupole tandem mass spectrometer Agilent 6460 combined with an Agilent 1200 HPLC-system as described before [28]. For these 8 experiments, microsomal incubations were performed exactly as described above; however, unlabelled AA and EPA were used as substrates.…”