Steroids with a carbamate function at C-17, a novel class of inhibitors for human and hamster steroid 5alpha-reductase.
In order to study the biological activity of the two novel steroidal carbamates derivatives: 8a and 8b, we determined the concentration of both compounds that inhibit the 50% of the activity of human prostate 5alpha-reductase enzyme, as well as the in vivo effect of these compounds in the weight of hamster prostate and flank organs diameter size. We determined also, the capacity of these steroids to bind to the androgen receptors present in the rat prostate cytosol. Furthermore the activity of these compounds on the mRNA expression of glycerol 3-phosphate acyl transferase (GPAT) in flank organs was analyzed by RT-PCR. This enzyme induces the triglycerides synthesis, which is increased by T in flank organs. The results from this study indicated that steroids 8a and 8b inhibited the human 5alpha-reductase activity. Compound 8b, which contains a bromine atom in the molecule, decreased the inhibitory effect of the human 5alpha-reductase activity, whereas steroid 8a, which lacks a halogen atom did not show any decrease in the activity of this enzyme. The competition studies demonstrated that 8a and 8b did not inhibit mibolerone binding to the androgen receptor present in the rat prostate cytosol. However, the in vivo activity of both steroids was similar; steroids 8a and 8b had a tendency to decrease the weight of the hamster prostate although this parameter was not statistically significant. These compounds also significantly reduced the diameter of the pigmented spot of hamster flank organs, which are androgen dependent skin's pilosebaceous structures. Steroids 8a and 8b, decreased the transcription of mRNA encoding for GPAT in intact hamster's flank organs topically treated in a similar way as in gonadectomized non-treated animals. These results suggest that mRNA encoding for GPAT is induced by DHT in this tissue.
Bratoeff
Eugene
E
Department of Pharmacy, Faculty of Chemistry, National University of Mexico City, Mexico, D.F., Mexico.
Sainz
Teresita
T
Cabeza
Marisa
M
Heuze
Ivonne
I
Recillas
Sergio
S
Pérez
Victor
V
Rodríguez
César
C
Segura
Tania
T
Gonzáles
Juan
J
Ramírez
Elena
E
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000378:metabolism*; D058891:5-alpha Reductase Inhibitors; D000818:Animals; D002219:Carbamates / Q000737:chemistry / Q000494:pharmacology*; D006224:Cricetinae; D004789:Enzyme Activation; D005992:Glycerol-3-Phosphate O-Acyltransferase / Q000378:metabolism*; D006801:Humans; D008297:Male; D008647:Mesocricetus; D009277:Nandrolone / Q000031:analogs & derivatives / Q000494:pharmacology; D011374:Progesterone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D011467:Prostate / Q000187:drug effects / Q000201:enzymology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011944:Receptors, Androgen / Q000378:metabolism
C525135:17-p-bromophenylcarbamoyloxypregn-4-ene-3,20-dione; C525134:17-phenylcarbamoyloxypregn-4-ene-3,20-dione; D058891:5-alpha Reductase Inhibitors; D002219:Carbamates; D012333:RNA, Messenger; D011944:Receptors, Androgen; D011374:Progesterone; D009277:Nandrolone; C100075:mibolerone; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; D005992:Glycerol-3-Phosphate O-Acyltransferase