Mechanism for the Inhibitory Effect of a Seleno-Organic Compound, Ebselen, and Its Analogues on Superoxide Anion Production in Guinea Pig Polymorphonuclear Leukocytes

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Effects of Ebselen and its analogs (PZ-25,NAT06-123,Nat02-761,Nat02-801,NAT06-099,and NAT06-513) on superoxide anion (O^-_2) production induced by tetradecanoyl phorbol acetate (TPA) were examined in intact guinea pig polymorphonuclear leukocytes (PMNL). Four compounds having a structure of 1,2 benzoisoselenazol-3-(2H) one (Ebselen, NAT06-123,and NAT02-761) and its sulfur-substituted analog (PZ-25), had a potent inhibitory effect on O^-_2 production as compared with others. Ebselen and NAT06-123 also markedly inhibited nicotinamide adenine dinuclestide phosphate (NADPH) oxidase activity, which is responsible for O^-_2 production in intact cells, and in a particulate fraction prepared from TPA-stimulated PMNL, whereas PZ-25 inhibited this enzyme weakly and NAT02-761 did not. On the other hand, Ebselen and PZ-25 had the same degree of potent inhibitory effect on protein kinase C which was involved in the regulation of NADPH oxidase activation. Thus, it is plausible that inhibition of O^-_2 production in intact PMNL by these compounds were due not only to direct inhibition of NADPH oxidase but also to inhibition of protein kinase C.
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