HUMAN PHARMACOLOGY OF DOCOSAHEXAENOIC ACID OXIDATION

Vanderbilt University, Nashville TN

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Abstract

Significant evidence implicates increased consumption of omega-3 polyunsaturated fatty acids (PUFAs),[unreadable] particularly docosahexaenoic acid (DHA), in the prevention of human diseases such as atherosclerosis.[unreadable] The mechanism by which DHA is protective is unknown although studies suggest that non-enzymatic[unreadable] oxidation products of DHA are anti-inflammatory. Nonetheless, these compounds have not been identified.[unreadable] In the previous cycle of this grant, we defined the free radical-initiated peroxidation of cholesteryl[unreadable] arachidonate in the context of atherosclerosis and have proposed a unified mechanism for its oxidation.[unreadable] The major peroxidation products consist of novel compounds containing mono- and serial cyclic peroxide[unreadable] and endoperoxide (isoprostane, IsoP) moieties. These compounds possess potent pro-inflammatory[unreadable] bioactivity and likely mediate various physiological and pathophysiological processes. Unlike arachidonate,[unreadable] the oxidation of DHA is predicted to be significantly more complex since it contains two additional carboncarbon[unreadable] unsaturated bonds. Studies proposed will examine the human pharmacology of DHA peroxidation[unreadable] in the context of atherosclerosis. We hypothesize the oxidation of DHA can be defined and results in the[unreadable] formation of compounds that contribute to the anti-inflammatory properties of this PUFA. The structural and[unreadable] mechanistic work will use docosahexaenoyl-glycerophosphatidylethanolamine (DHA-PE), because it is a[unreadable] major biologically relevant form and offers a unique opportunity to define the peroxidation of DHA in a[unreadable] physiologically relevant context. In addition, this will allow for the development of approaches to accurately[unreadable] characterize complex phospholipid oxidation products. A detailed study of the peroxidation of DHA, or for[unreadable] that matter any PUFA, esterifed in glycerophospholipids has not been undertaken.[unreadable] In Specific Aims 1 and 2, we will define mechanistically the free radical-initiated peroxidation of[unreadable] DHA-PE using novel chromatographic and mass spectrometric approaches.[unreadable] In Specific Aim 3, we will determine the effect of various factors, including novel antioxidants that we[unreadable] have developed, on the formation of different DHA-PE peroxidation products in vitro and in vivo.[unreadable] In Specific Aim 4, we will examine the inflammatory-mediating properties of DHA and selected[unreadable] peroxidation products. We will study the extent to which DHA decreases the formation of pro-inflammatory[unreadable] eicosanoids in animals and humans and also to what degree it reduces atherosclerosis in mouse models.[unreadable] Finally, we will examine the anti-inflammatory properties of one highly reactive DHA-derived[unreadable] cyclopentenone-containing IsoP-like compound formed in abundance in vivo, 4-A4t-neuroprostane.[unreadable] We contend that studies identifying novel oxidation products of DHA-PE and examining[unreadable] mechanisms by which these compounds are formed in vivo will yield insights into the role of this PUFA in[unreadable] human physiology and pathophysiology.