Antiandrogenic and apoptotic effects of RU-486 on animal prostate.
Mifepristone (RU-486) is a potent antagonist of steroid hormone receptors such as glucocoticoid and progesterone receptors. This compound also is a very strong inducer of the interaction between androgen receptors and corepressors NCoR and SMRT and therefore could be used as selective receptor modulator. In this study we determined the relative binding affinity of RU-486 to androgen receptors (AR) obtained from rat prostate cytosol as well as the in vivo effect of different doses of RU-486 on the prostate weight of hamsters treated with dihydrotestosterone and/or RU-486. We determined also the prostate cell death (apoptosis) in hamster treated with, dihydrotestosterone (DHT) and/or RU-486. The results of this study indicated that the relative binding affinity of RU-486 for AR is 4.3%. The data from the in vivo experiments also showed that RU-486 inhibited the prostate weight significantly in the highest doses thus indicating the antagonistic action of this compound on hamster prostate. The immunohistochemistry analysis showed that after 1 month of castration, the hamster prostate was atrophic. Treatment with DHT produced epithelial cell activity (measured by the increase in the prostate weight) and very low rate of apoptosis. When DHT was administered together with RU-486 (10 mg/kg) no change was observed. On the other hand, DHT plus higher doses of RU-486 (40, 80 mg/kg) resulted in an increase of apoptosis in stromal and secretory epithelial cells. In addition to the increase of the prostate cell apoptosis produced by the treatment with high dose of RU-486, other factors could contribute to the decrease of the prostate weight observed. Another possibility could be a reduction in the ductal fluid due to poor epithelial cell secretory activity more than apoptosis itself. Furthermore, in this experiment, RU-486 could have inhibited the growth of the prostate gland produced by DHT in a greater extent than the induction of atrophy and cell death. This fact could depend on the doses used, due to the low affinity of this compound for the androgen receptors.
Cabeza
Marisa
M
Department of Biological Systems and Animal Production Metropolitan University-Xochimilco, Mexico D.F., Mexico. marisa@correo.xoc.uam.mx
Bratoeff
Eugene
E
Heuze
Ivonne
I
Guzmán
Adrián
A
Gómez
Georgina
G
Berrios
Hilda
H
Rosales
Ana María
AM
D000726:Androgen Antagonists / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D006224:Cricetinae; D013196:Dihydrotestosterone / Q000494:pharmacology; D004347:Drug Interactions; D007150:Immunohistochemistry; D008297:Male; D015735:Mifepristone / Q000494:pharmacology*; D011467:Prostate / Q000187:drug effects*; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D011944:Receptors, Androgen / Q000378:metabolism
D000726:Androgen Antagonists; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D015735:Mifepristone