5α-reductase isozymes in castration-recurrent prostate cancer

Intracrine biosynthesis of dihydrotestosterone is the final step in anabolic androgen metabolism in the prostate. The NADPH-dependent steroid 5α-reductase isozymes irreversibly catalyze 5α-reduction of intracellular testosterone to dihydrotestosterone. In castration-recurrent prostate cancer mean mRNA levels suggest relative gene expression gradients of 5α-reductase-3 > 5α-reductase-1 ≫ 5α-reductase-2. Furthermore, sufficient levels of testosterone and dihydrotestosterone were observed in castration-recurrent prostate cancer to activate androgen receptor signaling pathway. In intact and recurrent CWR22 human xenografts, persistent dihydrotestosterone formation was observed after pretreatment with dutasteride. Improved inhibitors that target 5α-reductase-1, 2 and 3 isozymes may stop intraprostatic DHT biosynthesis and prevent the development of clinical prostate cancer or its progression.