S-oxygenation of 7 alpha-thiomethylspironolactone by the flavin-containing monooxygenase

Liver microsomes and highly purified flavin-containing monooxygenase from uninduced hogs catalyze the NADPH and oxygen-dependent S-oxygenation of 7 alpha-thiomethylspironolactone (7 alpha-TMSL), the major urinary metabolite of spironolactone, an effective antimineralocorticoid in humans. Studies on the biochemical mechanism of S-oxygenation of 7 alpha-TMSL suggests that this reaction is catalyzed exclusively by the flavin-containing monooxygenase and not by cytochrome P-450. This conclusion is based on the effects of selective cytochrome P-450 inhibitors as well as positive effectors and alternate substrates for the flavin-containing monooxygenase. The modest degree of stereoselective S-oxygenation of 7 alpha-TMSL may suggest steric inhibition of oxidation by the flavin-containing monooxygenase.