73 research outputs found
Substrate Selectivity of 5-Hydroxyeicosanoid Dehydrogenase and Its Inhibition by 5-Hydroxy-Δ6-Long-Chain Fatty Acids
5-Oxo-6E,8Z,11Z,14Z-eicosatetraenoic
acid (5-oxo-ETE) is a metabolite of the 5-lipoxygenase (5-LO) product
5S-hydroxy-6E,8Z,11Z,14Z-eicosatetraenoic
acid (5-HETE), formed by the microsomal enzyme 5-hydroxyeicosanoid
dehydrogenase (5-HEDH). 5-oxo-ETE is a chemoattractant for neutrophils and
eosinophils, both in vitro and in vivo. To examine the substrate selectivity
of 5-HEDH and to search for potential inhibitors, we prepared a series of
5S-hydroxy fatty acids (C12 to C20 containing
zero to four double bonds) by total chemical synthesis and examined their
metabolism by microsomes from monocytic U937 cells. Although most of these
fatty acids were oxidized to their 5-oxo metabolites by 5-HEDH, 5-HETE seemed
to be the best substrate. However, substrates containing less than 16 carbons,
a methylated α-carboxyl group, or a hydroxyl group at the ω-end of
the molecule were not substantially metabolized. Some of the fatty acids
tested were fairly potent inhibitors of the formation of 5-oxo-ETE by 5-HEDH,
in particular 5-hydroxy-6-octadecenoic acid and 5-hydroxy-6-eicosenoic acid.
Both substances selectively inhibited 5-oxo-ETE formation by human peripheral
blood mononuclear cells incubated with arachidonic acid and calcium ionophore
without affecting the formation of leukotriene B4, 12-HETE, or
12-hydroxy-5,8,10-heptadecatrienoic acid. We conclude that the requirements
for appreciable metabolism by 5-HEDH include a chain length of at least 16
carbons, a free α-carboxyl group, and a hydrophobic group at the
ω-end of the molecule. 5-Hydroxy-Δ6 C18 and
C20 fatty acids selectively inhibit 5-HEDH without inhibiting 5-LO,
leukotriene A4 hydrolase, 12-lipoxygenase, or cyclooxygenase. Such
compounds may be useful in defining the role of 5-oxo-ETE and its mechanism of
synthesis
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