PubMed · 1319540
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S Heinzl. 1992. [Target enzyme].. https://pubmed.ncbi.nlm.nih.gov/1319540/
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We have discovered that 17beta-[N,N-(diethyl)carbamoyl]-6-azaandrost-4-en-3-one is a time-dependent inhibitor of type II 5alpha-reductase, as is the drug finasteride. Unlike finasteride, the 6-aza-steroid is not a time-dependent inhibitor of type I 5 alpha-reductase. Finasteride inhibition of type II enzyme proceeds in a two-step mechanism. At pH 6 and 37 degrees C, an initial finasteride-reductase complex is formed with a K(i)(app) of 11.9 +/- 4.1 nM. In a second step, an irreversible complex is formed with a rate constant of inactivation of 0.09 +/- 0.01 s(-1). In contrast, the 6-aza-steroid is a reversible inhibitor. From the results of a simplified mathematical analysis, based on the rapid equilibrium approximation, the inhibitor and the enzyme form an initial complex with a K(i) of 6.8 +/- 0.2 nM. The reversible formation of a final complex, with an overall K(i) of 0.07 +/- 0.02 nM, is characterized by a first-order isomerization rate constant 0.0035 +/- 0.0001 s(-1) for the forward step and 0.00025 +/- 0.00006 s(-1) for the backward step. All rate constants for the two-step mechanism were obtained by using a general numerical integration method. The best fit values for the association and dissociation rate constants were 5.0 microM(-1) s(-1) and 0.033 +/- 0.008 s(-1), respectively, and the isomerization rate constants were 0.0035 +/- 0.007 s(-1) and 0.000076 +/- 0.000019 s(-1). These values correspond to an initial K(i) of 6.5 nM and an overall dissociation constant of 0.14 nM. The data presented here show that both finasteride and the 6-aza-steroid analogs are potent against type II 5alpha-reductase, although their mechanisms of inhibition are different.
The effects of various means of interfering with androgen action on rat coagulating gland, ventral prostate, lateral type 1 prostate, lateral type 2 prostate, and dorsal prostate were examined morphologically and quantitatively by assessing DNA content, wet weight, protein content, and zinc concentrations. Adult male Sprague-Dawley rats were subjected to 2 weeks of interfering with androgen action by treatment with Leuprolelin (a luteinizing hormone-releasing hormone analog), Finasteride (a 5 alpha-reductase inhibitor), or diethylstilbestrol (DES), or by physical castration. For all prostatic lobes, inhibition of 5 alpha-reductase elicited the smallest reduction in prostatic wet weight, DNA and protein contents, and zinc concentration. The most profound reductions in all parameters were elicited by castration. Treatments with DES and Leuprolelin gave intermediate effects with DES being the more effective in reducing all parameters in all prostatic lobes. Morphological changes elicited by all forms of androgen blockade were reduction of epithelial height, relative increase of connective tissue, reduction in ductal diameter, length, and number. The order of effectiveness of the various treatments on morphological features was as described above. While all forms of androgen blockade elicited similar effects throughout the prostate, differences in response to all forms of interference with androgen action were observed in different lobes of the prostate with regard to wet weight, DNA and protein contents, and zinc concentration as well as morphological effects. Regressive changes at the morphological level were particularly striking in the coagulating gland and ventral prostate, and indistinct in the lateral type 2 prostate. Prostatic zinc concentration in both normal and androgen-deprived rats was the highest in the lateral type 2 prostate and was reduced by interfering with androgen action to the greatest extent in the dorsolateral prostate (lateral type 1 and type 2, and dorsal prostate). The distribution of zinc correlated with the expression of metallothionein, which was detected by immunocytochemistry only in the lateral type 2 prostate of both normal and androgen deprived rats. Intraprostatic heterogeneity of zinc and metallothionein expression emphasizes interlobar differences in biological function within the rat prostate. The mechanism of development of regional heterogeneity within the prostate may shed light on the pathogenesis of prostatic proliferative diseases (prostatic hyperplasia and prostatic cancer) that initially owe their development to focal changes within large cell populations.
CGP 53153 (N-2-(cyano-2-propyl)-3-oxo-4-aza-5alpha-androst-1-ene-17beta-carb oxamide) is a steroidal inhibitor of 5alpha-reductase, the enzyme which effects the conversion of testosterone (T) to 5alpha-dihydrotestosterone (DHT). In vitro, CGP 53153 competitively inhibited rat microsomal 5alpha-reductase from prostate by 50% (IC50) at a concentration of 36nM compared to the reference compound finasteride which inhibited 5alpha-reductase with an IC50 of 11 nM in the same system. In vivo, inhibition of 5alpha-reductase activity was characterized in three different test systems. Inhibition of 5alpha-reductase activity was first assessed in a standard test designed to compare directly the potency of different 5alpha-reductase inhibitors. This test assesses potency through the inhibition of prostate growth in juvenile castrate male rats treated with a standard dose of T-propionate (1 mg/kg, s.c.) and a 5alpha-reductase inhibitor administered orally at various doses for 4 days. CGP 53153 and finasteride significantly reduced T-propionate-mediated prostate growth by about 25% (ED25) compared to T-propionate-treated controls at oral doses of 0.01 and 0.1 mg/kg, respectively. Second, the effects on prostate weight were studied in normal adult male rats treated orally once daily for 14 days with 1, 3 and 10 mg/kg CGP 53153 and with 10 mg/kg finasteride. CGP 53153 significantly reduced prostate weight at 3 and 10 mg/kg by 31% and 37%, respectively, compared to vehicle-treated controls, whereas the dose of 10 mg/kg finasteride did not significantly reduce prostate weight. Third, the effects on prostate volume were studied in normal 6-9-year-old male dogs treated orally once daily with 5 mg/kg CGP 53153 and with 5 mg/kg finasteride for 12 weeks. Prostate volume was monitored with magnetic resonance imaging every 2 weeks beginning 6 weeks before start of the treatment with 5alpha-reductase inhibitors and ending after a recovery period of 8 weeks after termination of treatment. Treatment for 12 weeks with both CGP 53153 and finasteride was equally effective in reducing prostate volume by more than 70% in individual dogs. Anti-androgenic potency of CGP 53153 and finasteride was assessed in juvenile castrate male rats treated with DHT-propionate (1 mg/kg, s.c.) and a 5alpha-reductase inhibitor (p.o.) for 4 days. Neither CGP 53153 nor finasteride given at a dose of 10 mg/kg had any significant effect on DHT-propionate-mediated prostate growth, whereas the reference anti-androgen flutamide given at a dose of 10 mg/kg reduced prostate weight to levels comparable to those seen in untreated castrate animals. For CGP 53153, the dose of 10 mg/kg is 1000-fold higher than the ED25 for 5alpha-reductase inhibition in vivo. In conclusion, both CGP 53153 and finasteride are potent inhibitors of the rat 5alpha-reductase enzyme system in vitro without showing any anti-androgenic effects in vivo. Both CGP 53153 and finasteride were equally potent in reducing prostate volume in aged male dogs, whereas in rats, CGP 53153 is up to 10 times more potent than finasteride in reducing prostate weight as shown in two different rat models.