Deactivation of sulindac-sulphide by human renal microsomes

The renal metabolism of sulindac-sulphide was studied in subcellular fractions from human kidney. It was shown that renal microsomes, in the presence of NADPH, effectively catalyzed the sulphoxidation of sulindac-sulphide. Also the mitochondrial fraction catalyzed the reaction but at a ten-fold lower rate than the microsomes. Carbon monoxide, metyrapone and n-octylamine did not inhibit renal sulphoxidation of sulindac-sulphide and the reaction could occur in a monooxygenase containing fraction free from NADPH-cytochrome P-450 reductase. Hydroxylation of lauric acid was studied in microsomes and in the purified monooxygenase containing fraction under the same experimental condition as sulindac-sulphide sulphoxidation. Lauric acid is a substrate known to be metabolized by a renal cytochrome P-450 to 11 and 12-hydroxylated products. This reaction was sensitive to carbon monoxide and did not occur in the absence of NADPH cytochrome P-450 reductase. Based on these results we conclude that cytochrome P-450 plays at the most a limited role in human kidney metabolism of sulindac-sulphide. In contrast, sulphoxidation of sulindac-sulphide was substantially reduced in the presence of methimazole suggesting a role of the flavin-containing monooxygenase in the renal biotransformation of sulindac-sulphide in man.