Tissue-specific pharmacology of testosterone and 5 alpha-dihydrotestosterone analogues: characterization of a novel canine liver androgen-binding protein.
The mechanism by which the hormones 5 alpha-dihydrotestosterone and testosterone differentially regulate such diverse functions as development of male internal and external genitalia and maintenance of prostatic growth via a single androgen receptor (AR) is not well understood. To search for potential AR isoforms, an extensive pharmacological survey of the binding of [3H]mibolerone (7 alpha,17 alpha-[3H]dimethyl-19-nortestosterone) in dog prostate, adrenal gland, testis, liver, kidney, brain, muscle, and spleen cytosolic extracts was carried out. The antagonist androst-4-en-3,17-dione (ATD), as well as a series of unsaturated analogues of testosterone, exhibited marked tissue specificity for binding to mibolerone-binding proteins (MBPs), with ATD having a 10-fold higher affinity for the MBPs present in liver than for those in prostate and testis. The difference in affinity was not due to tissue-specific metabolism of ATD. Competition binding profiles for ATD with mixtures of prostate and liver extracts were consistent with two distinct populations of binding sites. Both wild-type human AR-B and the recently discovered human AR-A isoform were expressed in COS cells and were found to exhibit pharmacology similar to that of the prostatic MBPs in dogs. Analogues of ATD or testosterone could prove to be useful probes for delineating the differential effects of 5 alpha-dihydrotestosterone and testosterone on the biological actions of the AR and related proteins.
Summerfield
A E
AE
Department of Molecular Pharmacology and Biochemistry, Merck Research Laboratories, Rahway, New Jersey 07065-0900, USA.
Diaz Cruz
P J
PJ
Dolenga
M P
MP
Smith
H E
HE
Strader
C D
CD
Toney
J H
JH
D000727:Androgen-Binding Protein / Q000378:metabolism*; D000818:Animals; D001141:Aromatase / Q000378:metabolism; D001667:Binding, Competitive; D002460:Cell Line; D003001:Cloning, Molecular; D003600:Cytosol / Q000378:metabolism; D013196:Dihydrotestosterone / Q000031:analogs & derivatives* / Q000494:pharmacology; D004285:Dogs; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D009277:Nandrolone / Q000031:analogs & derivatives / Q000378:metabolism; D011869:Radioligand Assay; D011944:Receptors, Androgen / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D013739:Testosterone / Q000494:pharmacology*; D045165:Testosterone Congeners / Q000378:metabolism; D014018:Tissue Distribution
D000727:Androgen-Binding Protein; D011944:Receptors, Androgen; D045165:Testosterone Congeners; D013196:Dihydrotestosterone; D013739:Testosterone; D009277:Nandrolone; C100075:mibolerone; D001141:Aromatase