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

被引:97
作者
Bauman, DR
Steckelbroeck, S
Williams, MV
Peehl, DM
Penning, TM
机构
[1] Univ Penn, Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA
[2] Stanford Univ, Sch Med, Dept Urol, Stanford, CA 94305 USA
关键词
D O I
10.1210/me.2005-0287
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Androgen-dependent prostate diseases initially require 5 alpha-dihydrotestosterone (DHT) for growth. The DHT product 5 alpha-androstane-3 alpha, 17 beta-diol (3 alpha-diol), is inactive at the androgen receptor (AR), but induces prostate growth, suggesting that an oxidative 3 alpha-hydroxysteroid dehydrogenase (HSD) exists. Candidate enzymes that posses 3 alpha-HSD activity are type 3 3 alpha-HSD (AKR1C2), 11-cis retinol dehydrogenase (RODH5), L-3-hydroxyacyl coenzyme A dehydrogenase, RODH like 33 alpha-HSD (RL-HSD), novel type of human microsomal 3 alpha-HSD, and retinol dehydrogenase 4 ( RODH 4). In mammalian transfection studies all enzymes except AKR1C2 oxidized 3 alpha-diol back to DHT where RODH 5, RODH 4, and RL-HSD were the most efficient. AKR1C2 catalyzed the reduction of DHT to 3 alpha-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 3 alpha-diol a 100-fold, yielding EC50 values of 2.5 x 10(-9) M, 1.5 x 10(-9) M, and 1.0 x 10(-9) M, respectively, when compared with the empty vector (EC50 = 1.9 x 10(-7) M). Real-time RT-PCR indicated that L-3-hydroxyacyl coenzyme 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 3 alpha-HSD in normal human prostate is RL-HSD and may be a new therapeutic target for treating prostate diseases.
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页码:444 / 458
页数:15
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