Effect of a 4‐methyl‐4‐aza steroid on androgen metabolism by rat ventral prostate epithelial and stromal cell cultures: Selective inhibition of 5α‐reductase activity

Abstract

The effect of a potent steroid metabolic inhibitor, 17β‐N,N‐diethylcarbamoyl‐4‐methyl‐4‐ aza‐5α‐androstan‐3‐one (DMAA), on androgen metabolism was investigated in primary monolayer cultures of rat ventral prostate epithelial and stromal cells. Using testosterone (T) as substrate, 5α‐reductase (5α‐R) activity in both cell types was inhibited by greater than 98% at an inhibitor concentration of 1000 nM. The concentrations required to produce a 50% inhibition (IC₅₀) were 7.4 and 9.0 nM for epithelial and stromal cells, respectively. To examine the specificity of this compound, its effect on other steroid‐metabolic enzymes was examined. DMAA at a concentration of 1,000 nM had no effect on 3α‐hydroxysteroid oxidase (3α‐HSORox), 3‐ketosteroid reductase (3α‐HSORred), and 6/7‐hydroxylase (6/7‐HSH) activities in both cell types; 17β‐hydroxysteroid oxidase (17β‐HSORox) activity, located primarily in epithelial cells, also was not influenced by DMAA. In contrast, epithelial 3β‐hydroxysteroid oxidase (3β‐HSORox) and 3‐ketosteroid reductase (3β‐ HSORred) activities were inhibited by 65% (P < .001) and 58% (P > .05), respectively, albeit the latter result was not statistically significant. Stromal 3β‐HSORox and 3β‐ HSORred activities were negligible; hence the effect of the inhibitor on these enzymes could not be assessed. In conclusion, DMAA is a relatively selective and potent inhibitor of 5α‐R activity in primary cultures of rat ventral prostate epithelial and stromal cells and should be a useful compound for antagonizing androgen‐mediated actions in the prostate and other androgen target tissues.