Mechanism for the inhibitory effect of a seleno-organic compound, Ebselen, and its analogues on superoxide anion production in guinea pig polymorphonuclear leukocytes.
Effects of Ebselen and its analogs (PZ-25, NAT06-123, NAT02-761, NAT02-801, NAT06-099, and NAT06-513) on superoxide anion (O2-) 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 O2- production as compared with others. Ebselen and NAT06-123 also markedly inhibited nicotinamide adenine dinuclestide phosphate (NADPH) oxidase activity, which is responsible for O2- 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 O2- 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.
Wakamura
K
K
Department of Physiological Chemistry, Hiroshima University School of Medicine, Japan.
Ohtsuka
T
T
Okamura
N
N
Ishibashi
S
S
Masayasu
H
H
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology*; D004789:Enzyme Activation; D005260:Female; D006168:Guinea Pigs; D006736:Horses; D054833:Isoindoles; D009247:NADH, NADPH Oxidoreductases / Q000097:blood; D019255:NADPH Oxidases; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D016566:Organoselenium Compounds; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D012643:Selenium / Q000494:pharmacology*; D013268:Stimulation, Chemical; D013481:Superoxides / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001393:Azoles; D054833:Isoindoles; D016566:Organoselenium Compounds; D013844:Thiazoles; D013481:Superoxides; C061323:RP 63600; C060674:2-phenyl-1,2-benzisothiazol-3-(2H)-one; C042986:ebselen; C061322:RP 61605; D009247:NADH, NADPH Oxidoreductases; D019255:NADPH Oxidases; D011493:Protein Kinase C; D012643:Selenium; D013755:Tetradecanoylphorbol Acetate