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Inhibitory effects of MK‐886 on arachidonic acid metabolism in human phagocytes

1 We have investigated the inhibitory activity of compound MK‐886 (formerly L‐663,536), an indole derivative, on 5‐lipoxygenase product synthesis in various human phagocytes stimulated with either the ionophore A23187, in the presence and absence of exogenous arachidonic acid, or platelet‐activating factor (PAF). The lipoxygenase products were analysed by reversed‐phase h.p.l.c. 2 MK‐886 inhibited the formation of 5‐hydroxy‐eicosatetraenoic acid (5‐HETE), leukotriene B4 (LTB4), its ω‐oxidation products and 6‐trans‐isomers with an IC50 value of 10–14 nm in A23187‐stimulated neutrophils. In the same system, nordihydroguaiaretic acid (NDGA), AA‐861 and L‐655,240 showed IC50 values of 250–510, 110–420 nm and 1.7–3.9 μm, respectively. 3 MK‐886 inhibited 5‐lipoxygenase product synthesis in A23187‐stimulated blood eosinophils and monocytes, and in neutrophils primed with granulocyte‐macrophage colony‐stimulating factor and stimulated with PAF with IC50 values of 1–13 nm. 4 The inhibitory activity of MK‐886 was not reversed by addition of 10 μm arachidonic acid to A23187‐stimulated neutrophils. 5 Compound MK‐886 had no effect on 15‐lipoxygenase product synthesis in blood eosinophils and neutrophils up to a concentration of 1 μm. 6 At 100 nm compound MK‐886 had no significant effects on calcium ion mobilization, superoxide anion production and actin polymerization in neutrophils. 7 In conclusion, MK‐886 is a very potent and specific inhibitor of both LTB4 and LTC4 synthesis in various types of human phagocytes.