Effects of tenidap on superoxide-generating enzymes: Non-competitive inhibition of xanthine oxidase

Abstract 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 μg/mL tenidap. The kinetics of xanthine oxidase inhibition by tenidap were non-competitive; the K i of tenidap for xanthine oxidase was 11 μg/mL (34 μM). 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.