Androgen-dependent prostate diseases initially require 5α- dihydrotestosterone (DHT) for growth. The DHT product 5α-androstane- 3α,17β-diol (3α-diol), is inactive at the androgen receptor (AR), but induces prostate growth, suggesting that an oxidative 3α-hydroxysteroid dehydrogenase (HSD) exists. Candidate enzymes that posses 3α-HSD activity are type 3 3α-HSD (AKR1C2), 11-cis retinol dehydrogenase (RODH 5), L-3-hydroxyacyl coenzyme A dehydrogenase, RODH like 3α-HSD (RL-HSD), novel type of human microsomal 3α-HSD, and retinol dehydrogenase 4 (RODH 4). In mammalian transfection studies all enzymes except AKR1C2 oxidized 3α-diol back to DHT where RODH 5, RODH 4, and RL-HSD were the most efficient. AKR1C2 catalyzed the reduction of DHT to 3α-diol, suggesting that its role is to eliminate DHT. Steady-state kinetic parameters indicated that RODH 4 and RL-HSD were high-affinity, low-capacity enzymes whereas RODH 5 was a low-affinity, high-capacity enzyme. AR-dependent reporter gene assays showed that RL-HSD,RODH 5, and RODH 4 shifted the dose-response curve for 3α-diol a 100-fold, yielding EC50 values of 2.5 × 10-9 M, 1.5 × 10-9 M, and 1.0 × 10-9 M, respectively, when compared with the empty vector (EC 50 1.9 × 10-7 M). Real-time RT-PCR indicated that L-3-hydroxyacyl co-enzyme A dehydrogenase and RL-HSD were expressed more than 15-fold higher compared with the other candidate oxidative enzymes in human prostate and that RL-HSD and AR were colocalized in primary prostate stromal cells. The data show that the major oxidative 3α-HSD in normal human prostate is RL-HSD and may be a new therapeutic target for treating prostate diseases. Copyright © 2006 by The Endocrine Society.
CITATION STYLE
Bauman, D. R., Steckelbroeck, S., Williams, M. V., Peehl, D. M., & Penning, T. M. (2006). Identification of the major oxidative 3α-hydroxysteroid dehydrogenase in human prostate that converts 5α-androstane-3α,17β-diol to 5α-dihydrotestosterone: A potential therapeutic target for androgen-dependent disease. Molecular Endocrinology, 20(2), 444–458. https://doi.org/10.1210/me.2005-0287
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