Inhibition of 3α‐hydroxysteroid oxidoreductase and 5α‐reductase activity by antiandrogens and indomethacin in the rat prostate

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Abstract
We studied the effects of antiandrogens in vitro on inhibition of 3α‐hydroxysteroid oxidoreductase (3α‐HSOR) and 5α‐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 3α‐HSOR inhibitor. The IC50s of CA, CMA, IND, and TZP for 3α‐HSOR reductase in cytosol were about 5, 10, 10, and 100 μM, respectively, and inhibition was competitive. The IC50 of IND for 3α‐HSOR reductase in microsomes was 20 μM. The IC50s of other inhibitors were >100 μM, and inhibition was noncompetitive. The IC50s of CA, CMA, IND, and TZP for 3α‐HSOR oxidase in cytosol were > 100 μM, and inhibition was competitive or noncompetitive. Inhibition of 3α‐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 5α‐reductase in prostate homogenate were about 0.01, 200, and 200 μM, respectively.

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