Selective Inhibition of Prostatic Tumor 5α-Reductase by a 4-Methyl-4-aza-steroid¹

The effect of sodium 4-methyl-3-oxo-4-aza-5α-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 5α-reductase, 4-MAPC was equally as effective as 17β-N,N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one, reported to be a potent 5α-reductase inhibitor. Inhibition of 5α-reductase activity by 4-MAPC, but not by 17β-N,N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one, was accompanied by concomitant stimulation of 17β-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 5α-reductase are reconcilable with the responsiveness of androgen-sensitive malignant prostatic cells to hormonal therapy.