Potential activities of androgen metabolizing enzymes in human prostate.
The entire androgen metabolism of the human prostate is an integral part of the DHT mediated cellular processes, which eventually give rise to the androgen responsiveness of the prostate. Therefore, the potential activities of various androgen metabolizing enzymes were studied. Moreover, the impact of aging on the androgen metabolism and the inhibition of 5 alpha-reductase by finasteride were studied. In epithelium (E) and stroma (S) of normal (NPR) and hyperplastic human prostate (BPH), for each enzyme being involved in the conversion either of testosterone via DHT, 3 alpha- and 3 beta-diol to the C19O3-triols or from testosterone to androstenedione and vice versa, the amount (Vmax) and Michaelis constant (Km) were determined by Lineweaver-Burk plots. Furthermore, Vmax/Km quotients were calculated, which served as an index for the potential enzyme activity. 17 enzymes showed a mean Vmax/Km > or = 0.10. The top four were the 5 alpha-reductases in E and S of NPR and BPH. Among those, the highest activity was found in E of NPR (1.6 +/- 0.2). Moreover, in E a significant age-dependent decrease of 5 alpha-reductase activity occurred, whereas in stroma rather constant activities were found over the whole age range. Similar age-dependent alterations were found for the cellular DHT levels. Finally, the finasteride inhibition of 5 alpha-reductase (IC50;nM) was stronger in E (35 +/- 17) than in S (126 +/- 15). In conclusion, 5 alpha-reductase is: (a) the outstanding androgen metabolizing enzyme in NPR and BPH; (b) dictating the DHT enrichment in the prostate; (c) under the impact of aging; and (d) preferentially inhibited by finasteride in E.
Krieg
M
M
Institute of Clinical Chemistry, University Clinic Bergmannsheil, Bochum, Germany.
Weisser
H
H
Tunn
S
S
D000328:Adult; D000368:Aged; D000375:Aging; D000728:Androgens / Q000378:metabolism*; D042944:Cholestenone 5 alpha-Reductase; D013196:Dihydrotestosterone / Q000378:metabolism; D004848:Epithelium / Q000201:enzymology; D018120:Finasteride / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011467:Prostate / Q000201:enzymology*; D011470:Prostatic Hyperplasia / Q000201:enzymology*
D000728:Androgens; D013196:Dihydrotestosterone; D018120:Finasteride; D010088:Oxidoreductases; D042944:Cholestenone 5 alpha-Reductase