Kinetic Parameters of 5α-Reductase Activity in Stroma and Epithelium of Normal, Hyperplastic, and Carcinomatous Human Prostates*

Abstract

To study the influence of 5 alpha-reductase on the concentration of dihydrotestosterone in prostatic tissue, we measured the activity of this enzyme in stroma and epithelium from 15 normal, 50 hyperplastic, and 20 carcinomatous prostates. Maximum velocity (Vmax) and Km parameters based on the Lineweaver-Burk and Eadie-Hofstee transformations of the Michaelis-Menten equation were related to the stromal and epithelial concentrations of dihydrotestosterone. On the basis of relative Vmax values, there was 6-15 times more 5 alpha-reductase activity in stroma than in epithelium regardless of the histology of the prostate. Stromal enzyme activity also was unique in having a 2- to 5-fold larger mean Km value and greater resistance to competitive and noncompetitive inhibition. Despite the enrichment of 5 alpha-reductase activity in stroma, the dihydrotestosterone concentrations in the stromal and epithelial fractions were very similar. In addition, similar concentrations were found in the stromal fractions of hyperplastic and carcinomatous tissues, notwithstanding a 4-fold difference in the mean Vmax values. This anomaly occurred in association with a large disparity in mean Km values, i.e. 68.3 +/- 1.6 (+/- SE) nmol/L in hyperplasia vs. 23.0 +/- 2.9 nmol/L in carcinoma. The dissociation between parameters of 5 alpha-reductase activity and tissue dihydrotestosterone concentrations was apparent to some extent in benign prostatic hyperplasia, in which the lowest stromal androgen concentrations were found in prostates with the largest Vmax and Km values; also, a rise in stromal Km was almost invariably associated with a proportional increase in Vmax (correlation coefficient = 0.95). These data strongly suggest that the stromal and epithelial forms of 5 alpha-reductase are separate isoenzymes, and that the excess of 5 alpha-reductase in stroma does not promote accumulation of an abnormal amount of dihydrotestosterone. They also imply that both the augmentation of 5 alpha-reductase activity in hyperplastic stroma and the condition of benign hyperplasia of the prostate are mutual consequences of a primary increase in Km.

Differential expression of steroid 5α-reductase isozymes and association with disease severity and angiogenic genes predict their biological role in prostate cancer

“…Production of androgens in prostate cells occurs by the action of two isozymes, steroid 5a-reductase types I and II, encoded by the SRD5A1 and SRD5A2 genes respectively (Bruchovsky et al 1988, Bonkhoff et al 1996. Angiogenesis is regulated by several stimulating and inhibiting growth factors, the most potent stimulatory factor being vascular endothelial growth factor (VEGF; Leung et al 1989, Boddy et al 2005.…”

The effect of dutasteride on intraprostatic dihydrotestosterone concentrations in men with benign prostatic hyperplasia

“…3 Dihydrotestosterone (DHT), the primary androgen responsible for prostate growth, is synthesized from testosterone by type 1 and type 2 5a-reductase (5AR), both of which are expressed and active in the prostate. [4][5][6] There is a wealth of evidence for a key role of DHT in the development and progression of BPH. 7 Most notably, large-scale clinical trials have demonstrated that the 5AR inhibitors (5ARIs), finasteride and dutasteride -by suppressing DHT levels -provide significant reductions in prostate volume, improvements in flow rate and symptoms and a decrease in the risk of AUR and diseaserelated surgery in men with BPH.…”

Current status of 5α-reductase inhibitors in the treatment of benign hyperplasia of prostate

“…[31][32][33][34] exhibits increased expression of both type 1 and type 2 enzymes. [35,36] Immunohistochemical studies using 5α-reductase type 2-specific antibodies have demonstrated that this enzyme is primarily localized in the stroma of the gland. [37] The stromal cells have been considered to play a primary role in androgen-dependent prostatic growth.…”