Steroid 5α-reductases and 3α-hydroxysteroid dehydrogenases:: key enzymes in androgen metabolism

Androgen action in mammals can be regulated at the pre-receptor level by the intracellular formation and degradation of potent androgens, such as 5 alpha -dihydrotestosterone (5 alpha -DHT). In androgen target tissues (e.g. prostate), 5 alpha -DHT is formed from circulating testosterone by the action of the type 2 steroid 5 alpha -reductase (5 alpha -R) and its action is terminated by the action of a reductive 3 alpha -hydroxysteroid dehydrogenase (3 alpha -HSD) which forms the weak androgen 3 alpha -androstanediol. Oxidative 3a-HSD isoforms, however, can provide an alternative source of potent androgens by converting 3 alpha -androstanediol to 5 alpha -DHT. Working in concert, 5 alpha -Rs and 3 alpha -HSDs determine the amount and the type of androgen available for the androgen receptor and hence affect transcription of genes under androgen control. In peripheral tissues (e.g. liver), type I 5 alpha -R and reductive 3 alpha -HSD isoforms work consecutively to eliminate androgens and protect against hormone excess. Thus, different 5 alpha -R and 3 alpha -HSD isoforms participate in distinct anabolic and catabolic processes and their important roles in androgen action render them drug targets for the treatment of androgen-dependent diseases.