EXPRESSION CLONING AND CHARACTERIZATION OF OXIDATIVE 17-BETA-HYDROXYSTEROID AND 3-ALPHA-HYDROXYSTEROID DEHYDROGENASES FROM RAT AND HUMAN PROSTATE

Intracellular levels of active steroid hormones are determined by thei r relative rates of synthesis and breakdown. In the case of the potent androgen dihydrotestosterone, synthesis from the precursor testostero ne is mediated by steroid 5 alpha-reductase, whereas breakdown to the inactive androgens 5 alpha-androstane-3 alpha,17 beta-diol (3 alpha-ad iol), and androsterone is mediated by reductive 3 alpha-hydroxysteroid dehydrogenases (3 alpha-HSD) and oxidative 17 beta-hydroxysteroid deh ydrogenases (17 beta-HSD), respectively. We report the isolation by ex pression cloning of a cDNA encoding a 17 beta-HSD6 isozyme that oxidiz es 3 alpha-adiol to androsterone. 17 beta-HSD6 is a member of the shor t chain dehydrogenase/reductase family and shares 65% sequence identit y with retinol dehydrogenase 1 (RoDH1), which catalyzes the oxidation of retinol to ret inal. Expression of rat and human RoDH cDNAs in mamm alian cells is associated with the oxidative conversion of 3 alpha-adi ol to dihydrotestosterone. Thus, 17 beta-HSD6 and RoDH play opposing r oles in androgen action; 17 beta-HSD6 inactivates 3 alpha-adiol by con version 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 im portant mechanism by which the steady state level of a transcriptional effector can be regulated.