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 microM), A23187 (IC50 16.2 +/- 5.4 microM), and U46619 (IC50 7.8 +/- 2.4 microM). 20-HETE did not inhibit thrombin-induced aggregation. 2. The human platelet metabolized 20-HETE to a series of novel metabolites formed by cyclo-oxygenase 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 H2/thromboxane A2 receptor.
Hill
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Department of Pediatrics, National Jewish Center for Immunology and Respiratory Medicine, Denver, CO 80206.
Fitzpatrick
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Murphy
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D000328:Adult; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism; D001792:Blood Platelets / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D000242:Cyclic AMP / Q000378:metabolism; D005231:Fatty Acids, Unsaturated; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D006893:Hydroxyeicosatetraenoic Acids / Q000097:blood / Q000502:physiology*; D066298:In Vitro Techniques; D015539:Platelet Activation / Q000502:physiology; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000378:metabolism; D044262:Prostaglandin H2; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011463:Prostaglandins H / Q000378:metabolism; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis
D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D006893:Hydroxyeicosatetraenoic Acids; D010975:Platelet Aggregation Inhibitors; D011463:Prostaglandins H; D044262:Prostaglandin H2; D013928:Thromboxane A2; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; C045749:SQ 29548; D000242:Cyclic AMP; D001092:Arachidonate 12-Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases