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

Abstract

Enzymic transformationof testosterone to the potent androgen, 5cr-dihydrotestosterone, has been shown by incubation of testosterone-4-W 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 Sol-androstanediol from 5adihydrotestosterone was also shown after longer incubation.Purified nuclear preparations of human skin seemed to possess little or no testosterone 5a-reductase activity, in contrast to similar preparations of rat prostate.The testosterone 5areductase in skin microsomes exhibited a Km of 1.1 x lop6 for testosterone.A number of steroids were found to inhibit the Sac-reduction of testosterone.Among these the most potent inhibitor was progesterone, which was converted into 5a-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 10VG M, indicating a slightly greater affinity of this steroid for the 5a-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 A4-3-keto structure, a 17p but not 17~1 substituent, and no modification or other substitutions in the steroid nucleus.A previous study from our la,boratory (1) showed the transformation of testosterone into 5wdihydrotestosteronel in human skin.Since 5wdihydrotestosteronc is a more potent sndrogen than testosterone by assays utilizing the seminal vesicle and