Expression cloning and characterization of oxidative 17 beta- and 3 alpha-hydroxysteroid dehydrogenases from rat and human prostate

Intracellular levels of active steroid hormones are determined by their relative rates of synthesis and breakdown. In the case of the potent androgen dihydrotestosterone, synthesis from the precursor testosterone is mediated by steroid 5 alpha-reductase, whereas breakdown to the inactive androgens 5 alpha-androstane-3 alpha,17 beta-diol (3 alpha-adiol), and androsterone is mediated by reductive 3 alpha-hydroxysteroid dehydrogenases (3 alpha-HSD) and oxidative 17 beta-hydroxysteroid dehydrogenases (17 beta-HSD), respectively. We report the isolation by expression cloning of a cDNA encoding a 17 beta-HSD6 isozyme that oxidizes 3 alpha-adiol to androsterone. 17 beta-HSD6 is a member of the short chain dehydrogenase/reductase family and shares 65% sequence identity with retinol dehydrogenase 1 (RoDH1), which catalyzes the oxidation of retinol to ret inal. Expression of rat and human RoDH cDNAs in mammalian cells is associated with the oxidative conversion of 3 alpha-adiol to dihydrotestosterone. Thus, 17 beta-HSD6 and RoDH play opposing roles in androgen action; 17 beta-HSD6 inactivates 3 alpha-adiol by conversion to androsterone and RoDH activates 3 alpha-adiol by conversion to dihydrotestosterone. The synthesis of an active steroid hormone by back conversion of an inactive metabolite represents a potentially important mechanism by which the steady state level of a transcriptional effector can be regulated.