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This version published online on September 22, 2005
Molecular Endocrinology, doi:10.1210/me.2005-0287
A more recent version of this article appeared on February 1, 2006
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*Compound via MeSH
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Medline Plus Health Information
*Prostate Diseases

Submitted on July 13, 2005
Accepted on September 12, 2005

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

David R. Bauman, Stephan Steckelbroeck, Michelle V. Williams, Donna M. Peehl, and Trevor M. Penning*

Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6084 and Department of Urology, Stanford University School of Medicine, Stanford, CA 94305

* To whom correspondence should be addressed. E-mail: penning{at}pharm.med.upenn.edu.

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 (RODH 5), L-3-hydroxyacyl coenzyme A dehydrogenase (ERAB), RODH like 3{alpha}-HSD (RL-HSD), novel type of human microsomal 3{alpha}-HSD (NT 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 while 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 ERAB 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 co-localized 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.
Key words: oxidase • androgen receptor • retinol dehydrogenase • aldo-keto reductase • benign prostatic hyperplasia • prostate cancer

NURSA Molecule Pages Link:

Nuclear Receptors:   AR
Ligands:   Dihydrotestosterone



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