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Identification of the Major Oxidative 3-Hydroxysteroid Dehydrogenase in Human Prostate That Converts 5-Androstane-3,17ß-diol to 5-Dihydrotestosterone: A Potential Therapeutic Target for Androgen-Dependent Disease

Department of Pharmacology (D.R.B., S.S., M.V.W., T.M.P), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6084; and Department of Urology (D.M.P.), Stanford University School of Medicine, Stanford, California 94305

Address all correspondence and requests for reprints to: Trevor M. Penning, Department of Pharmacology, University of Pennsylvania School of Medicine, 130C John Morgan Building, 3620 Hamilton Walk, Philadelphia, Pennsylvania 19104-6084. E-mail: penning{at}pharm.med.upenn.edu.

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

NURSA Molecule Pages Link:

Nuclear Receptors:   AR

Ligands:   Dihydrotestosterone

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