PMID- 16179381
OWN - NLM
STAT- MEDLINE
DCOM- 20060518
LR  - 20180116
IS  - 0888-8809 (Print)
IS  - 0888-8809 (Linking)
VI  - 20
IP  - 2
DP  - 2006 Feb
TI  - 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.
PG  - 444-58
AB  - 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.
FAU - Bauman, David R
AU  - Bauman DR
AD  - Department of Pharmacology, University of Pennsylvania School of Medicine, 
      Philadelphia, Pennsylvania 19104-6084, USA.
FAU - Steckelbroeck, Stephan
AU  - Steckelbroeck S
FAU - Williams, Michelle V
AU  - Williams MV
FAU - Peehl, Donna M
AU  - Peehl DM
FAU - Penning, Trevor M
AU  - Penning TM
LA  - eng
GR  - P30 ES013508/ES/NIEHS NIH HHS/United States
GR  - 1R25-CA-10187-D1/CA/NCI NIH HHS/United States
GR  - R01 CA-90744/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20050922
PL  - United States
TA  - Mol Endocrinol
JT  - Molecular endocrinology (Baltimore, Md.)
JID - 8801431
RN  - 0 (Androgens)
RN  - 0 (Receptors, Androgen)
RN  - 08J2K08A3Y (Dihydrotestosterone)
RN  - 25126-76-5 (Androstane-3,17-diol)
RN  - EC 1.1.1.50 (3-alpha-Hydroxysteroid Dehydrogenase (B-Specific))
RN  - EC 1.3.1.- (short chain trans-2-enoyl-CoA reductase)
RN  - EC 1.6.- (NADH, NADPH Oxidoreductases)
RN  - EC 2.3.1.85 (Fatty Acid Synthases)
SB  - IM
MH  - 3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)/antagonists & 
      inhibitors/genetics/*metabolism
MH  - Androgens/*metabolism
MH  - Androstane-3,17-diol/*metabolism
MH  - Animals
MH  - Cells, Cultured
MH  - Dihydrotestosterone/*metabolism
MH  - Fatty Acid Synthases/genetics
MH  - Humans
MH  - Male
MH  - NADH, NADPH Oxidoreductases/genetics
MH  - Prostate/*enzymology/metabolism
MH  - Prostatic Diseases/drug therapy/*enzymology/metabolism
MH  - Receptors, Androgen/genetics
MH  - Transcriptional Activation
MH  - Transfection
EDAT- 2005/09/24 09:00
MHDA- 2006/05/19 09:00
CRDT- 2005/09/24 09:00
PHST- 2005/09/24 09:00 [pubmed]
PHST- 2006/05/19 09:00 [medline]
PHST- 2005/09/24 09:00 [entrez]
AID - me.2005-0287 [pii]
AID - 10.1210/me.2005-0287 [doi]
PST - ppublish
SO  - Mol Endocrinol. 2006 Feb;20(2):444-58. doi: 10.1210/me.2005-0287. Epub 2005 Sep 
      22.