PMID- 12810547
OWN - NLM
STAT- MEDLINE
DCOM- 20030722
LR  - 20171116
IS  - 0013-7227 (Print)
IS  - 0013-7227 (Linking)
VI  - 144
IP  - 7
DP  - 2003 Jul
TI  - Human type 3 3alpha-hydroxysteroid dehydrogenase (aldo-keto reductase 1C2) and 
      androgen metabolism in prostate cells.
PG  - 2922-32
AB  - Human aldo-keto reductases (AKRs) of the AKR1C subfamily function in vitro as 
      3-keto-, 17-keto-, and 20-ketosteroid reductases or as 3alpha-, 17beta-, and 
      20alpha-hydroxysteroid oxidases. These AKRs can convert potent sex hormones 
      (androgens, estrogens, and progestins) into their cognate inactive metabolites or 
      vice versa. By controlling local ligand concentration AKRs may regulate steroid 
      hormone action at the prereceptor level. AKR1C2 is expressed in prostate, and in 
      vitro it will catalyze the nicotinamide adenine dinucleotide (NAD(+))-dependent 
      oxidation of 3alpha-androstanediol (3alpha-diol) to 5alpha-dihydrotestosterone 
      (5alpha-DHT). This reaction is potently inhibited by reduced NAD phosphate 
      (NADPH), indicating that the NAD(+): NADPH ratio in cells will determine whether 
      AKR1C2 makes 5alpha-DHT. In transient COS-1-AKR1C2 and in stable PC-3-AKR1C2 
      transfectants, 5alpha-DHT was reduced by AKR1C2. However, the transfected AKR1C2 
      oxidase activity was insufficient to surmount the endogenous 
      17beta-hydroxysteroid dehydrogenase (17beta-HSD) activity, which eliminated 
      3alpha-diol as androsterone. PC-3 cells expressed retinol 
      dehydrogenase/3alpha-HSD and 11-cis-retinol dehydrogenase, but these endogenous 
      enzymes did not oxidize 3alpha-diol to 5alpha-DHT. In stable LNCaP-AKR1C2 
      transfectants, AKR1C2 did not alter androgen metabolism due to a high rate of 
      glucuronidation. In primary cultures of epithelial cells, high levels of AKR1C2 
      transcripts were detected in prostate cancer, but not in cells from normal 
      prostate. Thus, in prostate cells AKR1C2 acts as a 3-ketosteroid reductase to 
      eliminate 5alpha-DHT and prevents activation of the androgen receptor. AKR1C2 
      does not act as an oxidase due to either potent product inhibition by NADPH or 
      because it cannot surmount the oxidative 17beta-HSD present. Neither AKR1C2, 
      retinol dehydrogenase/3alpha-HSD nor 11-cis-retinol dehydrogenase is a source of 
      5alpha-DHT in PC-3 cells.
FAU - Rizner, Tea Lanisnik
AU  - Rizner TL
AD  - Department of Pharmacology, University of Pennsylvania School of Medicine, 3620 
      Hamilton Walk, Philadelphia, PA 19104-6084, USA.
FAU - Lin, Hsueh K
AU  - Lin HK
FAU - Peehl, Donna M
AU  - Peehl DM
FAU - Steckelbroeck, Stephan
AU  - Steckelbroeck S
FAU - Bauman, David R
AU  - Bauman DR
FAU - Penning, Trevor M
AU  - Penning TM
LA  - eng
GR  - CA 97044/CA/NCI NIH HHS/United States
GR  - DK 47015/DK/NIDDK NIH HHS/United States
GR  - DK 54925/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Endocrinology
JT  - Endocrinology
JID - 0375040
RN  - 0 (Isoenzymes)
RN  - 08J2K08A3Y (Dihydrotestosterone)
RN  - 25126-76-5 (Androstane-3,17-diol)
RN  - 3XMK78S47O (Testosterone)
RN  - EC 1.1.- (17-Hydroxysteroid Dehydrogenases)
RN  - EC 1.1.- (Hydroxysteroid Dehydrogenases)
RN  - EC 1.1.1.357 (AKR1C2 protein, human)
SB  - IM
MH  - 17-Hydroxysteroid Dehydrogenases/metabolism
MH  - Adenocarcinoma
MH  - Androstane-3,17-diol/chemistry/metabolism
MH  - Animals
MH  - Bone Neoplasms
MH  - COS Cells
MH  - Dihydrotestosterone/chemistry/metabolism
MH  - Epithelial Cells/cytology/enzymology
MH  - Gene Expression Regulation, Enzymologic
MH  - Humans
MH  - Hydroxysteroid Dehydrogenases/genetics/*metabolism
MH  - In Vitro Techniques
MH  - Isoenzymes/metabolism
MH  - Male
MH  - Prostate/cytology/*enzymology
MH  - Prostatic Neoplasms
MH  - Testosterone/chemistry/*metabolism
MH  - Tumor Cells, Cultured
EDAT- 2003/06/18 05:00
MHDA- 2003/07/23 05:00
CRDT- 2003/06/18 05:00
PHST- 2003/06/18 05:00 [pubmed]
PHST- 2003/07/23 05:00 [medline]
PHST- 2003/06/18 05:00 [entrez]
AID - 10.1210/en.2002-0032 [doi]
PST - ppublish
SO  - Endocrinology. 2003 Jul;144(7):2922-32. doi: 10.1210/en.2002-0032.