PHARMACOLOGY OF OMEGA-3 FATTY ACIDS IN MAN

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Many clinical studies are being carried out to see if enrichment of the Western diet with w-3 fatty acids found in fish oil will prevent the development of atherosclerosis and its complications. This notion is based on the epidemiologic suggestion that populations with a high dietary intake of such fatty acids (eg. Eskimos and coastal Japanese) have a low incidence of stroke and myocardial infarction. These data are amplified by the finding that Eskimos and volunteers who consume fish oil develop prolonged bleeding times and apparently altered platelet function ex vivo, since recent evidence strongly suggests a role for chronic platelet activation and endothelial damage in the development of atherosclerosis. Very few studies have been performed on the effects of fish oil (or eicosapentaenoic acid, EPA) supplementation on indices of platelet-vascular interactions which accurately reflect alterations in prostanoid metabolism in vivo, or which assess the effects of increased dietary EPA on the many pathways of arachidonic acid (AA) metabolism in intact animals or man. Since EPA supplementation probably will have different effects on antagonistic AA metabolic pathways (eg. proaggregatory) thromboxane vs antiaggregatory prostacyclin) the net biologic result of altering the prostaglandin precursor pool by dietary means is unpredictable. We propose to assess the effects of feeding w-3 fatty acids on in vivo production of AA and EPA derived prostanoids by measuring the excretion of urinary metabolites with state-of-the-art methods during fish oil feeding as well as to study alterations in leukotriene and hydroxy fatty acid metabolism induced in human cells by such feeding. After establishing the biochemical changes which take place in normal volunteers and asymptomatic atherosclerotics, we will attempt to assess changes in biologic function by investigating whether EPA supplementation lowers blood pressure in atherosclerotics with mild untreated hypertension and whether EPA influences the early or late phase bronchial responses after allergen challenge in allergic asthmatics. During these studies newly developed capillary column GC/negative ion chemical ionization MS methods will be employed to assess changes in the types and amounts of cyclo and lipoxygenase products released in vivo and by cells isolated from volunteers after EPA feeding. By clarifying the clinical pharmacology of w-3 fatty acids in man in regards to both the cyclo and lipoxygenase pathways, a rational basis for clinical applications can be developed, allowing well-designed clinical studies to assess their potential in modifying the cause of human disease.