Identification of the major oxidative 3alpha-hydroxysteroid dehydrogenase in human prostate that converts 5alpha-androstane-3alpha,17beta-diol to 5alpha-dihydrotestosterone: a potential therapeutic target for androgen-dependent disease

Mol Endocrinol. 2006 Feb;20(2):444-58. doi: 10.1210/me.2005-0287. Epub 2005 Sep 22.


Androgen-dependent prostate diseases initially require 5alpha-dihydrotestosterone (DHT) for growth. The DHT product 5alpha-androstane-3alpha,17beta-diol (3alpha-diol), is inactive at the androgen receptor (AR), but induces prostate growth, suggesting that an oxidative 3alpha-hydroxysteroid dehydrogenase (HSD) exists. Candidate enzymes that posses 3alpha-HSD activity are type 3 3alpha-HSD (AKR1C2), 11-cis retinol dehydrogenase (RODH 5), L-3-hydroxyacyl coenzyme A dehydrogenase , RODH like 3alpha-HSD (RL-HSD), novel type of human microsomal 3alpha-HSD, and retinol dehydrogenase 4 (RODH 4). In mammalian transfection studies all enzymes except AKR1C2 oxidized 3alpha-diol back to DHT where RODH 5, RODH 4, and RL-HSD were the most efficient. AKR1C2 catalyzed the reduction of DHT to 3alpha-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 3alpha-diol a 100-fold, yielding EC(50) 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 (EC(50) = 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 3alpha-HSD in normal human prostate is RL-HSD and may be a new therapeutic target for treating prostate diseases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 3-alpha-Hydroxysteroid Dehydrogenase (B-Specific) / antagonists & inhibitors
  • 3-alpha-Hydroxysteroid Dehydrogenase (B-Specific) / genetics
  • 3-alpha-Hydroxysteroid Dehydrogenase (B-Specific) / metabolism*
  • Androgens / metabolism*
  • Androstane-3,17-diol / metabolism*
  • Animals
  • Cells, Cultured
  • Dihydrotestosterone / metabolism*
  • Fatty Acid Synthases / genetics
  • Humans
  • Male
  • NADH, NADPH Oxidoreductases / genetics
  • Prostate / enzymology*
  • Prostate / metabolism
  • Prostatic Diseases / drug therapy
  • Prostatic Diseases / enzymology*
  • Prostatic Diseases / metabolism
  • Receptors, Androgen / genetics
  • Transcriptional Activation
  • Transfection


  • Androgens
  • Receptors, Androgen
  • Dihydrotestosterone
  • Androstane-3,17-diol
  • 3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)
  • short chain trans-2-enoyl-CoA reductase
  • NADH, NADPH Oxidoreductases
  • Fatty Acid Synthases