Effects of 4-hydroxyandrost-4-ene-3,17-dione and its metabolites on 5 alpha-reductase activity and the androgen receptor.
The steroidal aromatase inhibitor, 4-hydroxyandrost-4-ene-3,17-dione (4OHA) and its metabolites, 4-hydroxytestosterone (4OHT), 3 beta,17-dihydroxy-5 alpha-androstan-4-one (metabolite A) and 3 alpha, 17-dihydroxy-5 beta-androstan-4-one (metabolite B) were evaluated as inhibitors of the human prostatic 5 alpha-reductase enzyme and for binding to the rat prostatic androgen receptor. 4OHA and 4OHT were weak inhibitors of 5 alpha-reductase with IC50 values of 15-29 microM. Metabolites A and B had no significant inhibitory activity. 4OHA and metabolites A and B bound weakly to the androgen receptor. The binding affinities (RBA) relative to mibolerone (RBA = 100) were 0.085, 0.485 and 0.016, respectively. However, 4OHT (RBA = 75) was a more potent binder than the endogenous androgen 5 alpha-dihydrotestosterone (RBA = 66). The ability of these metabolites, in particular 4OHT, to bind to the androgen receptor may explain the in vivo androgenic activity of 4OHA.
Davies
J H
JH
Department of Urology, St. Georges Hospital, London, England, UK.
Shearer
R J
RJ
Rowlands
M G
MG
Poon
G K
GK
Houghton
J
J
Jarman
M
M
Dowsett
M
M
D058891:5-alpha Reductase Inhibitors; D059002:Androgen Receptor Antagonists; D000735:Androstenedione / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006915:Hydroxytestosterones / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D009277:Nandrolone / Q000031:analogs & derivatives / Q000494:pharmacology; D011467:Prostate / Q000201:enzymology / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011944:Receptors, Androgen / Q000378:metabolism*; D013329:Structure-Activity Relationship
D058891:5-alpha Reductase Inhibitors; D059002:Androgen Receptor Antagonists; D006915:Hydroxytestosterones; D011944:Receptors, Androgen; D000735:Androstenedione; D009277:Nandrolone; C100075:mibolerone; C014594:formestane