Kinetic parameters of 5 alpha-reductase activity in stroma and epithelium of normal, hyperplastic, and carcinomatous human prostates.
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.
Bruchovsky
N
N
Department of Cancer Endocrinology, University of British Columbia, Vancouver, Canada.
Rennie
P S
PS
Batzold
F H
FH
Goldenberg
S L
SL
Fletcher
T
T
McLoughlin
M G
MG
D000368:Aged; D000369:Aged, 80 and over; D042944:Cholestenone 5 alpha-Reductase; D013196:Dihydrotestosterone / Q000378:metabolism; D004848:Epithelium / Q000201:enzymology; D006801:Humans; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011374:Progesterone / Q000378:metabolism; D011467:Prostate / Q000201:enzymology*; D011470:Prostatic Hyperplasia / Q000201:enzymology*; D011471:Prostatic Neoplasms / Q000201:enzymology*; D011863:Radioimmunoassay
D013196:Dihydrotestosterone; D011374:Progesterone; D010088:Oxidoreductases; D042944:Cholestenone 5 alpha-Reductase