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Potential activities of androgen metabolizing enzymes in human prostate
1Institute of Clinical Chemistry, University Clinic Bergmannsheil, Bochum, Germany.
Abstract:
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.
Insights
5 alpha-reductase is the key enzyme in prostate androgen metabolism, driving DHT levels. Its activity decreases with age in epithelium but not stroma, and finasteride more potently inhibits it in the epithelium.
Area of Science:
- Andrology
- Enzymology
- Prostate Cancer Research
Background:
- Androgen metabolism is crucial for prostate cellular functions.
- Dihydrotestosterone (DHT) plays a central role in prostate androgen responsiveness.
- Understanding enzyme activity and aging's impact is vital for prostate health.
Purpose of the Study:
- To investigate androgen metabolizing enzyme activities in normal and hyperplastic prostate tissues.
- To determine the influence of aging on prostate androgen metabolism.
- To assess the inhibitory effect of finasteride on 5 alpha-reductase.
Main Methods:
- Quantification of enzyme kinetics (Vmax, Km) using Lineweaver-Burk plots.
- Calculation of Vmax/Km quotients as an index of potential enzyme activity.
- Determination of finasteride's 5 alpha-reductase inhibition (IC50) in prostate epithelium and stroma.
Main Results:
- 5 alpha-reductases exhibited the highest activity among 17 studied enzymes in both normal (NPR) and benign hyperplastic (BPH) prostates.
- Epithelial 5 alpha-reductase activity and DHT levels significantly decreased with age, unlike in stroma.
- Finasteride demonstrated stronger inhibition of 5 alpha-reductase in prostate epithelium compared to stroma.
Conclusions:
- 5 alpha-reductase is the predominant androgen metabolizing enzyme in the prostate, responsible for DHT enrichment.
- Prostate 5 alpha-reductase activity and DHT levels are significantly affected by aging, particularly in the epithelium.
- Finasteride preferentially inhibits 5 alpha-reductase in the prostate epithelium, suggesting targeted therapeutic potential.