RT Journal Article SR Electronic T1 The Nongenotropic Synthetic Ligand 4-Estren-3α17β-diol Is a High-Affinity Genotropic Androgen Receptor Agonist JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 744 OP 748 DO 10.1124/mol.104.005272 VO 67 IS 3 A1 V. Krishnan A1 H. A. Bullock A1 B. C. Yaden A1 M. Liu A1 R. J. Barr A1 C. Montrose-Rafizadeh A1 K. Chen A1 J. A. Dodge A1 H. U. Bryant YR 2005 UL http://molpharm.aspetjournals.org/content/67/3/744.abstract AB The nongenotropic ligand estren (Science 298:843–846, 2002) was evaluated for its transcriptional activity mediated by the human androgen receptor (AR). Our results show that estren can bind, translocate, transactivate, and regulate two known target genes of AR in androgen-responsive cell lines. Estren binds recombinant AR with 10-fold higher affinity than either estrogen receptor (ER)-α or ERβ. Estren-bound AR can translocate AR to the nucleus and stimulate the androgen response element-luciferase reporter activity with an efficacy similar to that of androgen. Estren also increased the expression of prostate-specific antigen (PSA) in a dose-dependent manner in human LnCaP cells. Using chromatin immunoprecipitation analysis, we show that the estren-bound AR coimmunoprecipitates with a region of the PSA gene promoter. Therefore, cotreatment with an AR antagonist, bicalutamide, blocked the estren-induced increase in PSA expression. In contrast, phosphoinositol 3-kinase inhibitor wortmannin, or extracellular signal-regulated kinase inhibitor 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophynyltio)butadiene (U0126), and ER antagonist ICI-182780 failed to block the effects of estren. In vivo analysis of estren's action on male-orchidectomized ICR mice revealed estren's AR agonist actions on the levator ani and seminal vesicle target tissues. Taken together, our results reveal the hitherto unidentified genotropic action of estren mediated by AR in androgen-responsive cells and tissues.