Further Studies on Testosterone 5α-Reductase of Human Skin: STRUCTURAL FEATURES OF STEROID INHIBITORS

Abstract

Abstract Inhibition of the microsomal testosterone 5α-reductase of human skin was studied with various steroids bearing structural resemblance to testosterone. Since three of the most potent inhibitors found, i.e. progesterone, deoxycorticosterone acetate, and 4-androsten-3-one-17β-carboxylic acid, were shown by kinetic studies to be competitive inhibitors of testosterone 5α-reduction, the degree of inhibition caused by the various steroids tested in this study has been related to structural features of the steroid-binding site of the enzyme. A strict requirement for a 3-keto-Δ4 structure was found for effective inhibitory activity of a steroid, suggesting a hydrophilic nature of the enzyme at the binding site in the vicinity of Ring A of the steroid molecule. A 17β (but not α) side chain containing one or more oxygen functional groups is another required feature of the inhibitory steroid molecule, suggesting another hydrophilic region on the enzyme at the point of attachment of the side chain. This region in contrast to the region around Ring A is likely to be open or flexible, in view of the larger allowable variations in size of the side chain without detriment to the inhibitory activity.