Differential effect of 5 alpha-reductase inhibition and castration on androgen-regulated gene expression in rat prostate.
Castration reduces prostate size and causes intraprostatic testosterone (T) and dihydrotestosterone (DHT) to fall to very low levels. 5 alpha-Reductase inhibition also reduces prostate size, but results in a marked increase in intraprostatic T levels. To compare the effects of 5 alpha-reductase inhibition and castration on prostate physiology, male Sprague-Dawley rats were left intact, castrated, or given the selective 5 alpha-reductase inhibitor finasteride for up to 9 days. To be sure that finasteride itself did not directly affect gene expression, an additional group of rats was castrated and given finasteride for 4 days. The prostates were weighed, intraprostatic RNA, DNA, and androgen levels were measured, and mRNAs for two androgen-regulated genes, prostate steroid-binding protein (PSBP; an androgen-induced gene) and testosterone-repressed prostate message (TRPM-2), were quantitated by Northern and slot blot analyses. Finasteride caused a 95% reduction in intraprostatic DHT levels and a 10-fold increase in intraprostatic T levels. Finasteride, as expected, caused a pronounced decrease in prostate weight (45% on day 4). DNA content fell correspondingly (48% on day 4). Intraprostatic DNA (micrograms of DNA per gland) on day 4 was 328 +/- 53 in control rats, 171 +/- 10 in finasteride-treated rats (P less than 0.001 compared to controls), 115 +/- 2 in castrated rats (P less than 0.05 compared to finasteride), and 107 +/- 43 in finasteride-treated plus castrated rats (P = NS compared to castration alone). There were no significant differences in DNA levels among the groups when expressed per mg prostate tissue, indicating that mean prostate cell size was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)
Rittmaster
R S
RS
Department of Medicine and Physiology, Dalhousie University, Halifax, Nova Scotia, Canada.
Magor
K E
KE
Manning
A P
AP
Norman
R W
RW
Lazier
C B
CB
D058891:5-alpha Reductase Inhibitors; D000727:Androgen-Binding Protein / Q000235:genetics; D000728:Androgens / Q000097:blood / Q000494:pharmacology*; D000736:Androstenes / Q000494:pharmacology; D000818:Animals; D001378:Azasteroids / Q000494:pharmacology; D051152:Clusterin; D004247:DNA / Q000378:metabolism; D018120:Finasteride; D005786:Gene Expression Regulation / Q000187:drug effects*; D006023:Glycoproteins / Q000235:genetics; D008297:Male; D018832:Molecular Chaperones; D009919:Orchiectomy; D009929:Organ Size; D011467:Prostate / Q000033:anatomy & histology / Q000378:metabolism*; D060789:Prostatein; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011919:Rats, Inbred Strains; D060765:Secretoglobins; D014598:Uteroglobin; D060788:Mammaglobin B
D058891:5-alpha Reductase Inhibitors; D000727:Androgen-Binding Protein; D000728:Androgens; D000736:Androstenes; D001378:Azasteroids; D051152:Clusterin; D004247:DNA; D018120:Finasteride; D006023:Glycoproteins; D018832:Molecular Chaperones; D060789:Prostatein; D012313:RNA; D012333:RNA, Messenger; D060765:Secretoglobins; D014598:Uteroglobin; C511484:Scgb1d2 protein, rat; C511483:Scgb1d4 protein, rat; C556468:Scgb2a1 protein, rat; D060788:Mammaglobin B