BIOLOGICAL-ACTIVITY AND METABOLISM OF 20-HYDROXYEICOSATETRAENOIC ACID IN THE HUMAN PLATELET

1 The cytochrome P-450 metabolite of arachidonic acid, 20-hydroxyeicosatetraenoic acid (20-HETE), was found to be a potent, dose-dependent inhibitor of platelet aggregation and inhibitor of thromboxane biosynthesis induced by arachidonic acid (IC50 5.2 +/- 1.5-mu-M), A23187 (IC50 16.2 +/- 5.4-mu-M), and U46619 (IC50 7.8 +/- 2.4-mu-M). 20-HETE did not inhibit thrombin-induced aggregation. 2 The human platelet metabolized 20-HETE to a series of novel metabolites formed by cyclooxygenase as well as lipoxygenase pathways. The structures of the metabolites were identified by mass spectrometry as 20-hydroxy-thromboxane B2, 12,17-dihydroxyheptadecatrienoic acid, 12,20-dihydroxyeicosatetraenoic acid, and 11,20-dihydroxyeicosatetraenoic acid. 3 The identification of the 11-hydroxy metabolite of 20-HETE suggests that 20-HETE is less efficiently cyclized to an endoperoxide intermediate by cyclo-oxygenase than is arachidonate. 4 Although some biological activity of 20-HETE may be related to competition with endogenous arachidonate for cyclo-oxygenase metabolism, the predominant mechanism of action of 20-HETE appears to be through antagonism of the prostaglandin H-2/thromboxane A2 receptor.