Selective inhibition of prostatic tumor 5 alpha-reductase by a 4-methyl-4-azasteroid.

The effect of sodium 4-methyl-3-oxo-4-aza-5 alpha-pregnane-20(s)-carboxylate (4-MAPC) on testosterone metabolism was investigated in rat and human prostates in organ culture. The general properties of the test system for androgen metabolism and response to inhibitors were in close agreement with in vivo observations. As an inhibitor of prostatic tumor 5 alpha-reductase, 4-MAPC was equally as effective as 17 beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one, reported to be a potent 5 alpha-reductase inhibitor. Inhibition of 5 alpha-reductase activity by 4-MAPC, but not by 17 beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one, was accompanied by concomitant stimulation of 17 beta-oxidation of testosterone. This differential effect was observed in explants of human prostatic carcinoma and benign prostatic hypertrophy containing a relatively high degree of glandular hyperplasia. It was also seen in explants of dorsolateral rat prostate but not in the ventral prostate. 4-MAPC exhibited low affinity for rat prostatic cytosol 8S androgen receptor. Steroid extraction of purified nuclei from inhibited rat tissues revealed substantial amounts of radioactivity derived from [3H]testosterone cochromatographed with other metabolites in addition to dihydrotestosterone. The endocrine changes produced by this inhibitor of 5 alpha-reductase are reconcilable with the responsiveness of androgen-sensitive malignant prostatic cells to hormonal therapy.