Identification of Novel Autoxidation Products of the ω-3 Fatty Acid Eicosapentaenoic Acid in Vitro and in Vivo

Abstract

Increased intake of fish oil rich in the -3 fatty acids eicosapentaenoic acid (EPA, C20:5 -3) and docosahexaenoic acid (DHA, C22:6 -3) reduces the incidence of human disorders such as atherosclerotic cardiovascular disease. However, mechanisms that contribute to the beneficial effects of fish oil consumption are poorly understood. Mounting evidence suggests that oxidation products of EPA and DHA may be responsible, at least in part, for these benefits. Previously, we have defined the free radical-induced oxidation of arachidonic acid in vitro and in vivo and have proposed a unified mechanism for its peroxidation. We hypothesize that the oxidation of EPA can be rationally defined but would be predicted to be significantly more complex than arachidonate because of the fact that EPA contains an addition carbon-carbon double bond. Herein, we present, for the first time, a unified mechanism for the peroxidation of EPA. Novel oxidation products were identified employing state-ofthe-art mass spectrometric techniques including Ag ؉ coordination ionspray and atmospheric pressure chemical ionization mass spectrometry. Predicted compounds detected both in vitro and in vivo included monocylic peroxides, serial cyclic peroxides, bicyclic endoperoxides, and dioxolane-endoperoxides.

Formation of Highly Reactive Cyclopentenone Isoprostane Compounds (A3/J3-Isoprostanes) in Vivo from Eicosapentaenoic Acid

“…The fragmenta-tion patterns of A 3 /J 3 -IsoPs are similar to F 3 -IsoPs, and, indeed, previously acquired information regarding the F 3 -IsoPs was extremely useful for the present work (16). In addition, based on previous studies with F 3 -IsoPs, we would hypothesize that the 5-series and 18-series A 3 /J 3 -IsoPs should predominate, given the ability of the other 4-series of A 3 /J 3 -IsoP regioisomers to further oxidize to yield novel dioxolane-IsoPs derived from EPA (22). But, as is evident from data presented in Fig.…”

“…The effect of fish oil supplementation on levels of A 2 -/J 2 -IsoPs derived from arachidonic acid oxidation was also studied, and we found that EPA supplementation significantly reduced their level of formation (p Ͻ 0.05, data not shown). In addition, it should be noted that we have previously undertaken studies to confirm the stability of EPA in the fish oil diet fed to rodents to ensure that the source of oxidized EPA products was not the diet and that they were generated in vivo (22). techniques have been developed to analyze intact phospholipids as well as oxidized phospholipids (23)(24)(25)(26)(27)(28).…”

n-3 Fatty Acid-Derived Lipid Mediators against Neurological Oxidative Stress and Neuroinflammation

“…In contrast, recent studies on the effects of prostaglandins (PGE 2 and PGE 3 ) and leukotrienes (LTB 4 and LTB 5 ) on endothelium permeability and mononuclear adhesion and migration across endothelial cell cultures indicate that PGE 3 produces more pronounced effects on trans-endothelial Evans blue-albumin (EBA) permeability than PGE 2 , and these effects are antagonized by EP 1 and EP 2 antagonists (Moreno, 2009). LTB 4 and LTB 5 produce a slight effect on EBA extravasation (Moreno, 2009;Yin et al, 2007). It is suggested that EPA and ARA compete for the same COX enzymes (Zhao et al, 2004;Phillis et al, 2006), but the rate of oxidation of EPA is only 10% of the ARA.…”

Dietary Effects of Oxidized Eicosapentaenoic Acid (EPA) and Intact EPA on Hepatic Steatosis Induced by a High-sucrose Diet and Liver-X-receptor α Agonist in Mice

“…Since EPA has five carbon double bonds in its structure, it is readily oxidized to various oxidation products in food and the human body 16,17 . Lipid oxidation has been proposed to be harmful to human health and food quality.…”