Effects of 4-hydroxyandrost-4-ene-3,17-dione and its metabolites on 5 alpha-reductase activity and the androgen receptor.

Abstract

The steroidal aromatase inhibitor, 4-hydroxyandrost-4-ene-3,17-dione (4OHA) and its metabolites, 4-hydroxytestosterone (4OHT), 3 beta,17-dihydroxy-5 alpha-androstan-4-one (metabolite A) and 3 alpha, 17-dihydroxy-5 beta-androstan-4-one (metabolite B) were evaluated as inhibitors of the human prostatic 5 alpha-reductase enzyme and for binding to the rat prostatic androgen receptor. 4OHA and 4OHT were weak inhibitors of 5 alpha-reductase with IC50 values of 15-29 microM. Metabolites A and B had no significant inhibitory activity. 4OHA and metabolites A and B bound weakly to the androgen receptor. The binding affinities (RBA) relative to mibolerone (RBA = 100) were 0.085, 0.485 and 0.016, respectively. However, 4OHT (RBA = 75) was a more potent binder than the endogenous androgen 5 alpha-dihydrotestosterone (RBA = 66). The ability of these metabolites, in particular 4OHT, to bind to the androgen receptor may explain the in vivo androgenic activity of 4OHA.