Arachidonic acid (AA) is metabolized in mammals by separate cyclooxygenase and lipoxygenase systems. The cyclooxygenase pathway produces prostaglandins, thromboxanes and prostacyclins. The physiological importance of these metabolites has been largely established. Until recently, there was little information on the functions of lipoxygenase pathway. In 1979, Samuelsson and coworkers indentified the structure of slow reacting substance (SRS), an important mediator in asthma and other hypersensitivity reactions, as leukotriene C, a 5-lipoxygenase metabolite of AA. The availability of selective lipoxygenase inhibitors would be important in elucidation of the physiological role of different lipoxygenases as well as having possible therapeutic applications. No inhibitor of the leucocyte lipoxygenase (involved in SRS formation) has yet been reported and the few platelet lipoxygenase inhibitors which have been described suffer from lack of selectivity. We have recently found that 15-hydroxyeicosatetraenoic acid is a potent and selective inhibitor of platelet lipoxygenase. Our proposed program therefore is designed to prepare various hydroxy positional isomers and examine their inhibitory potencies on different lipoxygenases, using both oxygen consumption measurements and analysis of the radioactive products formed from (1-14C)-AA. Various kinetic parameters will be measured in order to elucidate the mechanism of this inhibition. We will also determine the importance of the different structural features of the inhibitor such as the free hydroxyl and carboxyl groups, presence of double bonds and chain length of the fatty acid. We will use these lipoxygenase inhibitors to probe the physiological roles of the lipoxygenases involved in SRS formation and platelet aggregation. The information obtained from this work will provide a rational basis for the design of new and more effective lipoxygenase inhibitors having potential clinical applications. For example, the availability of a selective inhibitor of SRS-A formation would be useful in developing effective antiallergic drugs.