Testosterone metabolism in primary cultures of human prostate epithelial cells and fibroblasts.
We compare testosterone (T) metabolism in primary cultures of epithelial cells and fibroblasts separated from benign prostate hypertrophy (BPH) and prostate cancer tissues. In all cultures, androstenedione (delta 4) formed by oxidation of T by 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) represented 80% of the metabolites recovered. The amounts of 5 alpha-dihydrotestosterone (DHT), formed by reduction of T by 5 alpha-reductase (5 alpha-R), were small: 5 and 2% (BPH) and 8 and 15% (adenocarcinoma) for epithelial cells and fibroblasts, respectively. Northern blot analysis of total RNA from epithelial cells (BPH or adenocarcinoma) attributed the reductive activity to the 5 alpha-reductase type 1 isozyme and oxidative activity to the 17 beta-HSD type 2. In cancer fibroblasts, only little 17 beta-HSD type 2 mRNA was detected. The 5 alpha-reductase inhibitors, 4-MA (17 beta-(N,N-diethyl)carbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one) and finasteride, inhibited DHT formation with a preferential action of 4-MA on epithelial cells (BPH or adenocarcinoma) and of finasteride on fibroblasts from adenocarcinoma. Neither inhibitor acted on delta 4 formation. On the other hand, the lipido-sterol extract of Serenoa repens (LSESr, Permixon) inhibited the formation of all the T metabolites studied [IC50 S = 40 and 200 micrograms/ml (BPH) and 90 and 70 micrograms/ml (adenocarcinoma) in epithelial cells and fibroblasts, respectively]. These results have important therapeutic implications when selecting appropriate treatment options for BPH.
Laboratoire de Cancérologie Expérimentale, Faculté de Médecine Secteur Nord, Marseille, France.
S
S
Délos
J L
JL
Carsol
E
E
Ghazarossian
J P
JP
Raynaud
P M
PM
Martin
D015067:17-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism; D018195:Adenosarcoma / Q000378:metabolism / Q000473:pathology; D000735:Androstenedione / Q000378:metabolism; D001378:Azasteroids / Q000494:pharmacology; D015152:Blotting, Northern; D002478:Cells, Cultured; D042944:Cholestenone 5 alpha-Reductase; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D013196:Dihydrotestosterone / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005043:Etiocholanolone / Q000031:analogs & derivatives / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018120:Finasteride / Q000494:pharmacology; D006801:Humans; D008297:Male; D008579:Meningioma / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism; D010920:Placenta / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D012313:RNA / Q000032:analysis; D012333:RNA, Messenger; D013739:Testosterone / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D001378:Azasteroids; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D013196:Dihydrotestosterone; D013739:Testosterone; D000735:Androstenedione; D018120:Finasteride; C006576:androstane-3,17-dione; D012313:RNA; C031563:17-N,N-diethylcarbamoyl-4-methyl-4-azaandrostane-3-one; D005043:Etiocholanolone; D010088:Oxidoreductases; D015067:17-Hydroxysteroid Dehydrogenases; C032690:3-alpha-(17-beta)-hydroxysteroid dehydrogenase (NAD(+)); D042944:Cholestenone 5 alpha-Reductase