EFFECTS OF TENIDAP ON SUPEROXIDE-GENERATING ENZYMES - NONCOMPETITIVE 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 mediati ng inflammatory responses, the effects of tenidap on mammalian enzymes capable of generating superoxide were determined. Tenidap had no effe ct on the generation of superoxide by NADPH oxidase reconstituted from fractionated neutrophil lysates. However, significant inhibition of s uperoxide production by mixtures of hypoxanthine and xanthine oxidase was observed in the presence of 3-30 mu g/mL tenidap. The kinetics of xanthine oxidase inhibition by tenidap were non-competitive; the Ki of tenidap for xanthine oxidase was 11 mu g/mL (34 mu M). No inhibition of xanthine oxidase was observed in the presence of other known inhibi tors of cyclooxygenase. Inhibition of xanthine oxidase may be a hereto fore unrecognized mechanism of the antirheumatic effects of tenidap.