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Biological activity and metabolism of 20‐hydroxyeicosatetraenoic acid in the human platelet
Author(s) -
Hill Elizabeth,
Fitzpatrick Frank,
Murphy Robert C.
Publication year - 1992
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1992.tb14327.x
Subject(s) - arachidonic acid , hydroxyeicosatetraenoic acid , chemistry , metabolite , thromboxane a2 , prostaglandin h2 , biochemistry , thromboxane , platelet , metabolism , mechanism of action , lipoxygenase , prostaglandin , receptor , medicine , enzyme , in vitro
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 (IC 50 5.2 ± 1.5 μ m ), A23187 (IC 50 16.2 ± 5.4 μ m ), and U46619 (IC 50 7.8 ± 2.4 μ m ). 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 B 2 , 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 A 2 receptor.