Effects of tenidap on superoxide-generating enzymes. Non-competitive inhibition of xanthine oxidase.
The anti-rheumatic drug tenidap has been shown previously to attenuate superoxide production by activated neutrophils. Given the importance of leukocyte as well as endothelial cell derived superoxide in mediating inflammatory responses, the effects of tenidap on mammalian enzymes capable of generating superoxide were determined. Tenidap had no effect on the generation of superoxide by NADPH oxidase reconstituted from fractionated neutrophil lysates. However, significant inhibition of superoxide production by mixtures of hypoxanthine and xanthine oxidase was observed in the presence of 3-30 micrograms/mL tenidap. The kientics of xanthine oxidase inhibition by tenidap were non-competitive; the Ki of tenidap for xanthine oxidase was 11 micrograms/mL (34 microM). No inhibition of xanthine oxidase was observed in the presence of other known inhibitors of cyclooxygenase. Inhibition of xanthine oxidase may be a heretofore unrecognized mechanism of the antirheumatic effects of tenidap.
Chatham
W W
WW
Research Service, Department of Veterans Affairs, Birmingham, AL USA.
Baggott
J E
JE
Loose
L D
LD
Blackburn
W D
WD
D000243:Adenosine Deaminase / Q000378:metabolism; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D019271:Hypoxanthine; D007042:Hypoxanthines / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D007700:Kinetics; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors; D019255:NADPH Oxidases; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D000078183:Oxindoles; D013481:Superoxides / Q000378:metabolism*; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D007042:Hypoxanthines; D007211:Indoles; D000078183:Oxindoles; D013481:Superoxides; D019271:Hypoxanthine; C062866:tenidap; D014969:Xanthine Oxidase; D009247:NADH, NADPH Oxidoreductases; D019255:NADPH Oxidases; D000243:Adenosine Deaminase