To determine the effects of 4-hydroxy-4-androstene-3,17-dione (4-OH-A) on the in vitro conversion of testosterone (T) to 5 alpha-androstan-17 beta-ol-3-one (dihydrotestosterone, DHT), 5 alpha-androstan-3 alpha, 17 beta-diol and 5 alpha-androstan-3 beta, 17 beta-diol (diols), human benign hypertrophic prostatic (BPH) tissue was incubated with 4-14C-T as substrate, in the presence of 4-OH-A (10(-8) to 10(-6) M); the amounts of the 5 alpha-reduced metabolites formed were quantitated. The effects of 4-OH-A were compared with those of 17 beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one (4-MA), a known inhibitor of the 5 alpha-reductase. In the absence of 4-OH-A and 4-MA, human BPH tissue converted T to DHT and the diols readily. Both 4-OH-A and 4-MA induced significant and dose-related decreases in the formation of both DHT and the diols. The degree of inhibition induced by the different concentrations of 4-OH-A and 4-MA were 31, 41, 72% and 57, 87, 97%, respectively. The decreased formation of the diols was a consequence of the decreased availability of DHT (the immediate precursor of the diols) and was not due to direct effects of the inhibitors on the 3-hydroxysteroid dehydrogenases; both 4-OH-A and 4-MA were totally unable to modify the conversion of DHT to the diols, when 4-14C-DHT was used as substrate. Thus, 4-OH-A inhibits the process of 5 alpha-reduction of T in BPH tissue. This molecule might represent a potential new agent for the prevention and/or treatment of human BPH.
The present study reports the effects exerted by 4-hydroxy-4-androstene-3,17-dione (4-OH-A) on the in vitro metabolism of labelled testosterone, dihydrotestosterone (DHT) and androstenedione (delta-4-A) in the prostate of adult male rats and in human benign prostatic hypertrophic (BPH) tissue. It has been found that 4-OH-A decreases the formation of DHT and of the diols. When testosterone is used as the substrate, the presence in the medium of 4-OH-A enhances the formation of delta-4-A and of 5-alpha-androstane-dione (5-alpha-A); 4-OH-A does not inhibit the conversion of labelled DHT into the diols. Also, the transformation of labelled delta-4-A into 5-alpha-A is not modified by 4-OH-A. On the basis of these findings, it is suggested that 4-OH-A might represent a potential new agent for the prevention and/or treatment of human BPH.
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