In vitro studies on the effect of cofactors on the 5 alpha-reductase and 3 alpha- and 3 beta-hydroxysteroid reductase...

Many studies have intimated that the accumulation and hence elevation of dihydrotestosterone (DHT) in the human prostate may be the primary factor in the development of benign prostatic hyperplasia (BPH). This accumulation has been explained in terms of an increase in the 5 alpha-reductase enzymatic activity which converts testosterone to DHT and a decrease in the relative activities of the 3 alpha-HSORred and 3 beta-HSORred enzymes. To investigate this hypothesis further, the activities of these two enzymes were studied in the presence and absence of NADPH in benign hyperplastic tissue and in normal peripheral (NPR) and benign hyperplastic periurethral (BPH) tissue taken from the same prostate. The results of these studies demonstrate a several fold increase in the activities of 3 alpha-HSORred and 3 beta-HSORred in the presence of NADPH in the hyperplastic human prostate. This increase in the activities of these two enzymes is found to the same degree in normal peripheral and benign hyperplastic periurethral tissue taken from the same prostate. There was no difference in percent increase in 3 alpha- and 3 beta-diol formation from DHT with NADPH in normal peripheral versus benign hyperplastic periurethral prostatic tissue. In subsequent experiments, Vmax/Km, as an index of the enzymatic capacity of the 3 alpha-HSORred and 3 beta-HSORred enzymes, was determined in both NPR and BPH tissue in media fortified with one mM NADPH. This quotient was found to be essentially the same in NPR and BPH tissue for both the 3 alpha-HSORred and the 3 beta-HSORred. Subsequently, the Vmax/Km value for the 5 alpha-reductase in BPH tissue was found to be equal to the combined Vmax/Km values of the 3 alpha-HSORred and 3 beta-HSORred. The reverse reaction or the conversion of 5 alpha-androstane-3 alpha,17 beta-diol and 5 alpha-androstane-3 beta,17 beta-diol is completely blocked in a medium containing one mM NADPH. These studies suggest that the concentration of DHT in prostatic tissue is dependent on the level of NADPH necessary for the 3 alpha-HSORred and 3 beta-HSORred enzymes to convert DHT to its respective diols.