Transformation of Testosterone into 17β-Hydroxy-5α-androstan-3-one by Microsomal Preparations of Human Skin

Abstract

Abstract Enzymic transformation of testosterone to the potent androgen, 5α-dihydrotestosterone, has been shown by incubation of testosterone-4-14C with microsomal preparations of human neonatal foreskin. The activity was stimulated by NADPH but not by NADH, and the reaction proceeded optimally at pH 5.6. Formation of 5α-androstanediol from 5α-dihydrotestosterone was also shown after longer incubation. Purified nuclear preparations of human skin seemed to possess little or no testosterone 5α-reductase activity, in contrast to similar preparations of rat prostate. The testosterone 5α-reductase in skin microsomes exhibited a Km of 1.1 x 10-6 for testosterone. A number of steroids were found to inhibit the 5α-reduction of testosterone. Among these the most potent inhibitor was progesterone, which was converted into 5α-pregnane-3,20-dione, and competed effectively with testosterone for the active site of the enzyme. The Ki of progesterone was approximately 0.7 x 10-6 m, indicating a slightly greater affinity of this steroid for the 5α-reductase than that of testosterone. Other potent inhibitors tested were androstenedione and deoxycorticosterone, while estradiol, hydrocortisone, and the antiandrogen, testololactone, had no inhibitory effect. The necessary structural characteristics of an effective inhibitor seem to be a Δ4-3-keto structure, a 17β but not 17α substituent, and no modification or other substitutions in the steroid nucleus.