Inhibition of 3 alpha-hydroxysteroid oxidoreductase and 5 alpha-reductase activity by antiandrogens and indomethacin in the rat prostate.

We studied the effects of antiandrogens in vitro on inhibition of 3 alpha-hydroxysteroid oxidoreductase (3 alpha-HSOR) and 5 alpha-reductase activities in the rat prostate. Kinetic and inhibition experiments were analyzed by thin layer chromatography. Cyproterone acetate (CA), chlormadinone acetate (CMA), and TZP-4238 (TZP), which is more potent than other antiandrogens, were used as inhibitors and were compared with indomethacin IND, which is a recognized 3 alpha-HSOR inhibitor. The IC50S of CA, CMA, IND, and TZP for 3 alpha-HSOR reductase in cytosol were about 5, 10, 10, and 100 microM, respectively, and inhibition was competitive. The IC50 of IND for 3 alpha-HSOR reductase in microsomes was 20 microM. The IC50S of other inhibitors were > 100 microM, and inhibition was noncompetitive. The IC50S of CA, CMA, IND, and TZP for 3 alpha-HSOR oxidase in cytosol were > 100 microM, and inhibition was competitive or noncompetitive. Inhibition of 3 alpha-HSOR oxidation was not observed in microsomes. The difference between these inhibition patterns suggests that there may be 4 isoenzymes in rat prostatic tissue. The IC50S of MK-906, CMA, and TZP for 5 alpha-reductase in prostate homogenate were about 0.01, 200, and 200 microM, respectively.