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J. Biol. Chem., Vol. 265, Issue 3, 1436-1442, Jan, 1990
CA Rouzer, AW Ford-Hutchinson, HE Morton and JW Gillard
Recently, we have shown that ionophore activation of human leukocytes
results in leukotriene synthesis and a translocation of 5-lipoxygenase from
the cytosol to cellular membrane. This membrane translocation was
postulated to be an important early activation step for the enzyme. 3-
[1-(p-Chlorobenzyl)-5-(isopropyl)-3-tert-butylthioindol-2-yl]-2, 2-
dimethylpropanoic acid (MK886) is a potent and specific inhibitor of
leukotriene biosynthesis in vivo and in intact cells, but has no direct
effect on 5-lipoxygenase activity in cell-free systems. In this report, we
show that MK886 can both prevent and reverse the membrane translocation of
5-lipoxygenase, in conjunction with the inhibition of leukotriene
synthesis. Similar compounds of the indole class could also inhibit the
membrane translocation of 5-lipoxygenase in a rank order of potency that
correlated with their potencies for leukotriene synthesis inhibition. In
contrast L-656,224, a direct 5-lipoxygenase inhibitor, had no effect on the
translocation of the enzyme. Attempts to demonstrate the effects of MK886
on the association of 5-lipoxygenase with membrane in cell-free
preparations failed due to a nonspecific Ca2+-dependent sedimentation of
the enzyme. The mechanism of action of MK-886 is therefore to block
translocation, prevent subsequent activation of 5-lipoxygenase, and hence
block cellular leukotriene biosynthesis.
MK886, a potent and specific leukotriene biosynthesis inhibitor blocks and reverses the membrane association of 5-lipoxygenase in ionophore- challenged leukocytes
Department of Pharmacology, Merck Frosst Centre for Therapeutic Research, Pointe Claire-Dorval, Quebec, Canada.
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