Inhibition of 5a‐Reductase Activity and Alteration of Nuclear Testosterone

Abstract

17β-N, N-diethylcarbamoyl-4-methyl-4-aza-5α-an-drostan-3-one (4-MA) inhibits 5α-reductase activity in cultured human genital skin fibroblasts. Enzyme kinetic studies analyzed by Eadie-Hofstee plots demonstrated that 4-MA is a competitive inhibitor, with an apparent K_i of 15 nM. 4-MA had a very low binding affinity for the androgen receptor. When fibroblasts were incubated in the presence of testosterone (T) and 4-MA, nuclear uptake of 5α-dihydrotestosterone (DHT) decreased in parallel with the inhibition of 5?-reduc-tase activity. While the overall sum for the nuclear uptake of T and DHT diminished, the nuclear uptake of T increased. Biological androgen inactivity cannot be precluded on the basis of nuclear T plus DHT uptake.