Blockade of androstenedione-induced stimulation of androgen-sensitive parameters in the rat prostate by combination of Flutamide and 4-MA.
In order to mimic the human situation in which adrenal steroid precursors are converted to the active androgen dihydrotestosterone (DHT) in prostatic tissue, we have used castrated rats supplemented with the precursor steroid androstenedione (delta 4-dione) released from Silastic implants. While it is well known that the action of DHT can be partially neutralized by antiandrogens which compete for binding to the androgen receptor, we have used 17 beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one (4-MA), an inhibitor of 5 alpha-reductase, the enzyme which converts testosterone into DHT, in order to decrease intraprostatic DHT levels and thus facilitate the action of the antiandrogen. Animals were treated for 7 days with Flutamide (FLU, 2 mg) or 4-MA (4 mg) injected subcutaneously, twice daily, alone or in combination. 4-MA administered alone caused a 54% inhibition of delta 4-dione-stimulated ventral prostate weight while FLU exerted a 74% inhibitory effect and 4-MA+FLU further improved inhibition to 81%. We then measured, by in situ hybridization, the levels of prostatic mRNAs encoding the C1 and C3 components of the prostatic binding protein (PBP) which are highly specific and sensitive markers of androgen action. PBP-C3 mRNA levels fell by 95% following castration while treatment with delta 4-dione completely reversed the effect of castration. Administration of FLU or 4-MA independently caused 33% and 10% decreases, respectively, of PBP-C3 mRNA levels stimulated by delta 4-dione while the combination of both compounds further inhibited PBP-C3 mRNA levels to reach a 55% inhibition. Similar effects were observed on PBP-C1 mRNA levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Martel
C
C
MRC Group in Molecular Endocrinology, CHUL Research Center, Quebec, Canada.
Trudel
C
C
Couet
J
J
Labrie
C
C
Bélanger
A
A
Labrie
F
F
D058891:5-alpha Reductase Inhibitors; D000727:Androgen-Binding Protein / Q000235:genetics; D000728:Androgens / Q000494:pharmacology*; D000735:Androstenedione / Q000494:pharmacology*; D000818:Animals; D001378:Azasteroids / Q000494:pharmacology*; D013196:Dihydrotestosterone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D005485:Flutamide / Q000494:pharmacology*; D017403:In Situ Hybridization; D008297:Male; D009919:Orchiectomy; D009929:Organ Size / Q000187:drug effects; D049488:Phosphatidylethanolamine Binding Protein; D011467:Prostate / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism*; D060789:Prostatein; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D060765:Secretoglobins; D014598:Uteroglobin; D060788:Mammaglobin B
D058891:5-alpha Reductase Inhibitors; D000727:Androgen-Binding Protein; D000728:Androgens; D000735:Androstenedione; D001378:Azasteroids; D013196:Dihydrotestosterone; D005485:Flutamide; D049488:Phosphatidylethanolamine Binding Protein; D060789:Prostatein; D012333:RNA, Messenger; D060765:Secretoglobins; D014598:Uteroglobin; C511482:PEBP1 protein, human; C511484:Scgb1d2 protein, rat; C511483:Scgb1d4 protein, rat; C031563:17-N,N-diethylcarbamoyl-4-methyl-4-azaandrostane-3-one; C556468:Scgb2a1 protein, rat; D060788:Mammaglobin B