Contrasting effects of two arachidonate 5-lipoxygenase inhibitors on formyl-methionyl-leucyl-phenylalanine (fMLP) and complement fragment 5a induced human neutrophil superoxide generation.
SC-45662 and SC-41661A, selective arachidonate 5-lipoxygenase (5-LO) inhibitors, had markedly different effects on formyl-methionyl-leucyl-phenylalanine (fMLP) and complement fragment 5a (C5a) induced superoxide release from human neutrophils (PMNs). SC-45662 inhibited superoxide generation induced by fMLP and C5a with IC50 values of 12 and 5 microM, respectively. Furthermore, SC-45662 was capable of inhibiting fMLP and C5a induced superoxide release in PMNs primed with bacterial lipopolysaccharide, tumor necrosis factor-alpha and other priming agents. SC-41661A, a compound from the same chemical series as SC-45662, did not inhibit or induce superoxide generation, but instead primed PMNs for fMLP and C5a induced superoxide generation. The induced superoxide release was concentration dependently enhanced 2 to 4-fold at 5-50 microM. Superoxide release induced by phorbol myristate acetate or serum-activated zymosan was unaffected by either SC-45662 or SC-41661A. The regulation of superoxide generation by these compounds, both of which have the identical oxidation-reduction pharmacophore, was clearly independent of their effects on 5-LO activity. Furthermore, the mechanism by which SC-45662 and SC-41661A alter superoxide generation did not appear to depend on inhibition of xanthine oxidase, catalase or superoxide dismutase. These new compounds provide effective tools for further investigation of the relationship of these two biochemical oxidative systems.
Kocan
G P
GP
Infectious Diseases Research Department, Searle Research and Development, Skokie, IL 60077.
Partis
R A
RA
Mueller
R A
RA
Smith
W G
WG
Nakao
A
A
D000085:Acetates / Q000494:pharmacology; D000577:Amides / Q000494:pharmacology; D000818:Animals; D015936:Complement C5a / Q000494:pharmacology*; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D013481:Superoxides / Q000097:blood*; D014407:Tumor Cells, Cultured
D000085:Acetates; D000577:Amides; D016859:Lipoxygenase Inhibitors; D010636:Phenols; D011725:Pyridines; D013481:Superoxides; C066992:(2-((3,5-di-t-butyl-4-hydroxyphenyl)thio)-1-methylpropoxy)acetic acid; C081292:SC 41661A; D009240:N-Formylmethionine Leucyl-Phenylalanine; D015936:Complement C5a