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 omega-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 microM, 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 microM 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 microM. 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.
Ménard
L
L
Unité de recherche Inflammation et Immunologie-Rhumatologie, Centre Hospitalier de l'Université Laval, Laurier, Québec, Canada.
Pilote
S
S
Naccache
P H
PH
Laviolette
M
M
Borgeat
P
P
D000199:Actins / Q000378:metabolism; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003115:Colony-Stimulating Factors / Q000494:pharmacology; D004804:Eosinophils / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D020024:Leukotriene Antagonists; D015289:Leukotrienes / Q000096:biosynthesis; D009504:Neutrophils / Q000187:drug effects; D010586:Phagocytes / Q000187:drug effects / Q000378:metabolism*; D010972:Platelet Activating Factor / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D002722:Chlorobenzenes
D000199:Actins; D016718:Arachidonic Acid; D001095:Arachidonic Acids; D000001:Calcimycin; D002118:Calcium; D003115:Colony-Stimulating Factors; D007211:Indoles; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D010972:Platelet Activating Factor; D013481:Superoxides; C060893:MK-886; D002722:Chlorobenzenes; C052517:L 655240