Pre-receptor regulation of the androgen receptor.
The human androgen receptor (AR) is a ligand-activated nuclear transcription factor and mediates the induction of genes involved in the development of the male phenotype and male secondary sex characteristics, as well as the normal and abnormal growth of the prostate. We have identified the pair of hydroxysteroid dehydrogenases (HSDs) that regulate ligand access to the AR in human prostate. We find that type 3 3alpha-HSD (aldo-keto reductase (AKR)1C2) catalyzes the NADPH dependent reduction of the potent androgen 5alpha-dihydrotestosterone (5alpha-DHT) to yield the inactive androgen 3alpha-androstanediol (3alpha-diol). We also find that RoDH like 3alpha-HSD (RL-HSD) catalyzes the NAD(+) dependent oxidation of 3alpha-diol to yield 5alpha-DHT. Together these enzymes are involved in the pre-receptor regulation of androgen action. Inhibition of AKR1C2 would be desirable in cases of androgen insufficiency and inhibition of RL-HSD might be desirable in benign prostatic hyperplasia.
Center of Excellence in Environmental Toxicology, Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia 19104-6084, USA. penning@pharm.med.upenn.edu
Trevor M
TM
Penning
Yi
Y
Jin
Tea Lanisnik
TL
Rizner
David R
DR
Bauman
D000429:Alcohol Oxidoreductases / Q000378:metabolism / Q000502:physiology; D000449:Aldehyde Reductase; D000074408:Aldo-Keto Reductases; D000728:Androgens / Q000096:biosynthesis / Q000378:metabolism; D005786:Gene Expression Regulation; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D008024:Ligands; D008297:Male; D008954:Models, Biological; D008958:Models, Molecular; D011467:Prostate / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics*; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)
D000429:Alcohol Oxidoreductases; D000449:Aldehyde Reductase; D000074408:Aldo-Keto Reductases; D000728:Androgens; D006913:Hydroxysteroid Dehydrogenases; D008024:Ligands; D011944:Receptors, Androgen; C435496:AKR1C2 protein, human; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)