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Blood, Vol. 93 No. 3 (February 1), 1999:
pp. 1086-1096
Biological Inactivation of 5-oxo-6,8,11,14-Eicosatetraenoic
Acid by Human Platelets
William S. Powell,
Sylvie Gravel,
Subhash P. Khanapure, and
Joshua Rokach
From Meakins-Christie Laboratories, Department of Medicine, McGill
University, Montreal, Quebec, Canada; and the Claude Pepper Institute
and Department of Chemistry, Florida Institute of Technology,
Melbourne, FL.
Neutrophil-derived 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE)
is a potent activator of neutrophils and eosinophils. In the present
study we examined the biosynthesis and metabolism of this substance by
platelets. Although platelets contain an abundant amount of
5-hydroxyeicosanoid dehydrogenase, the enzyme responsible for the
formation of 5-oxo-ETE, they synthesize only very small amounts of this
substance from exogenous 5-hydroxyeicosatetraenoic acid (5-HETE) unless
endogenous NADPH is converted to NADP+ by
addition of phenazine methosulfate. Similarly, relatively small amounts
of 5-oxo-ETE were formed by A23187-stimulated mixtures of platelets and
neutrophils, which instead formed substantial amounts of two 12-hydroxy
metabolites of this substance, 5-oxo-12-HETE and 8-trans-5-oxo-12-HETE,
which were identified by comparison with authentic chemically
synthesized compounds. These metabolites were also formed from
5-oxo-ETE by platelets stimulated with thrombin or A23187. In contrast,
unstimulated platelets converted 5-oxo-ETE principally to 5-HETE.
Neither 5-oxo-12-HETE nor 8-trans-5-oxo-12-HETE had appreciable effects
on neutrophil calcium levels or platelet aggregation at concentrations
as high as 10 µmol/L, but both blocked 5-oxo-ETE-induced calcium
mobilization in neutrophils with IC50 values
of 0.5 and 2.5 µmol/L, respectively. We conclude that platelets can
biologically inactivate 5-oxo-ETE. Unstimulated platelets convert
5-oxo-ETE to 5-HETE, with a 99% loss of biological potency, whereas
stimulated platelets convert this substance to 12-hydroxy metabolites,
which possess antagonist properties.
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