TISSUE-SPECIFIC PHARMACOLOGY OF TESTOSTERONE AND 5-ALPHA-DIHYDROTESTOSTERONE ANALOGS - CHARACTERIZATION OF A NOVEL CANINE LIVER ANDROGEN-BINDING PROTEIN

The mechanism by which the hormones 5 alpha-dihydrotestosterone and te stosterone differentially regulate such diverse functions as developme nt of male internal and external genitalia and maintenance of prostati c growth via a single androgen receptor (AR) is not well understood. T o search for potential AR isoforms, an extensive pharmacological surve y of the binding of [H-3]mibolerone (7 alpha, 17 alpha-[H-3]dimethyl-1 9-nortestosterone) in dog prostate, adrenal gland, testis, liver, kidn ey, brain, muscle, and spleen cytosolic extracts was carried out. The antagonist androst-4-en-3,17-dione (ATD), as well as a series of unsat urated analogues of testosterone, exhibited marked tissue specificity for binding to mibolerone-binding proteins (MBPs), with ATD having a 1 0-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 dist inct populations of binding sites. Both wild-type human AR-B and the r ecently discovered human AR-A isoform were expressed in COS cells and were found to exhibit pharmacology similar to that of the prostatic MB Ps in dogs. Analogues of ATD or testosterone could prove to be useful probes for delineating the differential effects of 5 alpha-dihydrotest osterone and testosterone on the biological actions of the AR and rela ted proteins.