title: Effects of some novel inhibitors of C17,20-lyase and 5alpha-reductase in vitro and in vivo and their potential role in the treatment of prostate cancer.
abstract: The effects of some novel steroidal compounds were evaluated against both human C17,20-lyase and 5alpha-reductase in vitro and also against androgen synthesis in normal male rats. L-2, L-36, L-37, and I-41 showed potent inhibition of human testicular C17,20-lyase, with IC50s of 43, 39, 42, and 58 nM, respectively. In contrast, ketoconazole, a competitive inhibitor of C17,20-lyase, had an IC50 of 76 n.M. L-36 also showed potent inhibitory activity against 5a-reductase in human prostatic microsomes, with an IC50 of approximately 31 nM. The inhibitory activities of L-2 and 1-41 on 5alpha-reductase were moderate, with IC50s of 75 and 151 nM, respectively, whereas L-37 showed little inhibitory activity against this enzyme. In comparison, finasteride, a potent inhibitor of 5alpha-reductase, had an IC50 of 33 nM. When normal male rats were treated with these novel compounds (50 or 100 mg/kg/day) for 14 consecutive days, the wet weight of the prostate was significantly reduced by L-36, L-37, and I-41, compared to the control group. Testosterone levels in rat serum were also reduced by L-36 (55%), L-37 (86%), and I-41 (53%). The concentrations of testosterone in rat testes were reduced by these novel compounds by 13-74%. The compounds also reduced the concentration of testosterone in rat prostates by 35-75%. Similarly, dihydrotestosterone (DHT) concentration in rat serum was reduced 30-89% by these compounds, compared to the control group. Prostatic DHT levels were also lower in rats treated with L-36 (48%), L-37 (54%), or I-41 (26%). In contrast, L-2 enhanced serum testosterone and prostatic DHT concentrations by >50%. These findings suggest that the dual activities of several of these novel inhibitors of C17,20-lyase and 5alpha-reductase accounts for the diminished levels of circulating androgens in vivo.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, University of Maryland at Baltimore, 21201, USA.
authors.forename: I P
authors.initials: IP
authors.lastname: Nnane
authors.forename: K
authors.initials: K
authors.lastname: Kato
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.forename: Q
authors.initials: Q
authors.lastname: Lu
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.forename: Y Z
authors.initials: YZ
authors.lastname: Ling
authors.forename: A
authors.initials: A
authors.lastname: Brodie
mesh_terms: D000728:Androgens / Q000096:biosynthesis; D000818:Animals; D042944:Cholestenone 5 alpha-Reductase; D013196:Dihydrotestosterone / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D018120:Finasteride / Q000494:pharmacology; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D011467:Prostate / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors*; D013739:Testosterone / Q000378:metabolism
chemical_list: D000728:Androgens; D004791:Enzyme Inhibitors; D013196:Dihydrotestosterone; D013739:Testosterone; D018120:Finasteride; D010088:Oxidoreductases; D013254:Steroid 17-alpha-Hydroxylase; D042944:Cholestenone 5 alpha-Reductase; D007654:Ketoconazole