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
| Autor: | Stephan Steckelbroeck, David R. Bauman, Trevor M. Penning, Donna M. Peehl, Michelle V. Williams |
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| Rok vydání: | 2006 |
| Předmět: |
Male
Transcriptional Activation Prostatic Diseases endocrine system animal structures Coenzyme A Dehydrogenase Biology Transfection Retinol dehydrogenase chemistry.chemical_compound Endocrinology Oxidoreductase medicine Animals Humans NADH NADPH Oxidoreductases Molecular Biology Cells Cultured chemistry.chemical_classification Prostate Dihydrotestosterone General Medicine 3-alpha-Hydroxysteroid Dehydrogenase (B-Specific) Androstane-3 17-diol Molecular biology Androgen receptor Enzyme chemistry Biochemistry Receptors Androgen Androgens Androstane Fatty Acid Synthases medicine.drug |
| Zdroj: | Molecular Endocrinology. 20:444-458 |
| ISSN: | 1944-9917 0888-8809 |
| DOI: | 10.1210/me.2005-0287 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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