Identification of the molecular switch that regulates access of 5α-DHT to the androgen receptor

Pairs of hydroxysteroid dehydrogenases (HSDs) govern ligand access to steroid receptors in target tissues and act as molecular switches. By acting as reductases or oxidases, HSDs convert potent ligands into their cognate inactive metabolites or vice versa. This pre-receptor regulation of steroid hormone action may have profound effects on hormonal response. We have identified the HSDs responsible for regulating ligand access to the androgen receptor (AR) in human prostate. Type 3 3α-hydroxysteroid dehydrogenase (aldo-keto reductase 1C2) acts solely as a reductase to convert 5α-dihydrotestosterone (DHT), a potent ligand for the AR (Kd = 10−11 M for the AR), to the inactive androgen 3α-androstanediol (Kd = 10−6 M for the AR); while RoDH like 3α-HSD (a short-chain dehydrogenase/reductase (SDR)) acts solely as an oxidase to convert 3α-androstanediol back to 5α-DHT. Our studies suggest that aldo-keto reductase (AKRs) and SDRs function as reductases and oxidases, respectively, to control ligand access to nuclear receptors.