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
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
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DOI：
10.1210/me.2005-0287
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发表时间：
2006-02-01
影响因子：
--
通讯作者：
Penning, TM
中科院分区：
文献类型：
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作者：
Bauman, DR;Steckelbroeck, S;Penning, TM
雄激素依赖性前列腺疾病最初需要5 -二氢睾酮（DHT）来生长。DHT产物5 α -雄甾烷-3 α， 17 β -二醇（3 α -二醇），雄激素受体（AR）无活性，但可诱导前列腺生长，提示存在氧化3 α -羟基类固醇脱氢酶（HSD）。具有3 α - hsd活性的候选酶有3型3 α - hsd （AKR1C2）、11-顺式视黄醇脱氢酶（RODH5）、l -3-羟酰基辅酶A脱氢酶、rodh33 α - hsd （RL-HSD）、新型人微体3 α - hsd和视黄醇脱氢酶4 （RODH 4）。在哺乳动物转染研究中，除AKR1C2外，所有酶都将3 α -二醇氧化回DHT，其中RODH 5、RODH 4和RL-HSD效率最高。AKR1C2催化DHT还原为3 α -二醇，提示其作用是消除DHT。稳态动力学参数表明，rodh4和RL-HSD为高亲和力、低容量酶，而rodh5为低亲和力、高容量酶。ar依赖性报告基因检测显示，与空载体（EC50 = 1.9 x 10(-7) M）相比，RL-HSD、RODH 5和RODH 4将3 α -二醇的剂量-反应曲线移动了100倍，EC50值分别为2.5 × 10(-9) M、1.5 × 10(-9) M和1.0 × 10(-9) M。Real-time RT-PCR结果显示，l- 3-羟酰基辅酶A脱氢酶和RL-HSD在人前列腺中的表达量比其他候选氧化酶高15倍以上，RL-HSD和AR在原代前列腺基质细胞中共定位。结果表明，正常人前列腺中主要的氧化性3 α - hsd为RL-HSD，可能成为治疗前列腺疾病的新靶点。
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.