title: The phytoestrogen genistein is a tissue-specific androgen receptor modulator.
abstract: To enable studies of androgen signaling in different tissues in vivo, we generated an androgen receptor (AR) reporter mouse line by inserting a luciferase gene construct into the murine genome. The construct is driven by four copies of androgen-responsive elements from the mouse sex-limited protein gene (slp-HRE2) and a minimal thymidine kinase promoter. Luciferase activity was readily measurable in a number of murine tissues, including prostate, lung, testis, brain, and skeletal muscle, and testosterone administration elicited a significant increase in reporter gene activity in these tissues. Consumption of isoflavonoid genistein is linked to reduced risk of prostate cancer, but direct effects of genistein on the AR pathway are not well understood. To examine androgen-modulating activity of genistein in vivo, male mice received daily doses of genistein (10 mg/kg) for 5 d. In intact males, genistein was antiandrogenic in testis, prostate, and brain, and it attenuated reporter gene activity by 50-80%. In castrated males, genistein exhibited significant androgen agonistic activity in prostate and brain by increasing reporter gene activity over 2-fold in both tissues. No antiandrogenic action was seen in lung or skeletal muscle of intact males. Gene expression profiling of the murine prostate under the same experimental conditions revealed that genistein modulates androgen-dependent transcription program in prostate in a fashion similar to that observed in reporter mice by luciferase expression. In conclusion, genistein is a partial androgen agonist/antagonist in some but not in all mouse tissues and should be considered as a tissue-specific AR modulator.
authors: Institute of Biomedicine, Physiology, Biomedicum Helsinki, University of Helsinki, and Department of Clinical Chemistry, Helsinki University Central Hospital, P.O. Box 63, FI-00014 Helsinki, Finland.
authors: Päivi
authors: P
authors: Pihlajamaa
authors: Fu-Ping
authors: FP
authors: Zhang
authors: Lilli
authors: L
authors: Saarinen
authors: Laura
authors: L
authors: Mikkonen
authors: Sampsa
authors: S
authors: Hautaniemi
authors: Olli A
authors: OA
authors: Jänne
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D017930:Genes, Reporter / Q000187:drug effects; D019833:Genistein / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009928:Organ Specificity; D048789:Phytoestrogens / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011467:Prostate / Q000187:drug effects* / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013737:Testis / Q000187:drug effects* / Q000378:metabolism
chemical_list: D048789:Phytoestrogens; D011944:Receptors, Androgen; D019833:Genistein