Endocrinology, 2011, 152(11):4395-405.

The Phytoestrogen Genistein Is a Tissue-Specific Androgen Receptor Modulator

Fu Ping Zhang, et al

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.

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.

美国《内分泌学》，2011年11月

植物性雌激素金雀异黄素是一种组织特异性雄激素受体调节剂

张富平等

芬兰赫尔辛基大学生物医学和生理学研究所以及赫尔辛基大学中心医院临床化学系

为了能够在体内不同组织研究雄性激素信号通路，通过将一种荧光素酶基因结构插入到小鼠基因组中，我们制造了一种雄激素受体的(AR) 记录老鼠曲线。这种结构产生自四份老鼠限制性别的蛋白基因 (slp-HRE2)的雄激素反应元素和最小的胸苷激酶启动子。荧光素酶的活性可以在多种小鼠组织中轻易测得，包括前列腺、 肺、 睾丸、 大脑和骨骼肌，并且在这些组织中睾酮给药会引起记录基因活性的明显增加。异黄酮染料木黄酮的消耗直接与前列腺癌风险的减少有关，但是金雀异黄素对 AR 通路的直接影响还不太清楚。为了测试染料木黄酮在体内调节雄激素的活性，雄性小鼠接受了为期5 天每天剂量为10 mg/kg的金雀异黄素。对于完整雄性，染料木素在睾丸、 前列腺癌、 和大脑中是抗雄激素的，并且它可以减弱记录基因活性的 50-80%。对于去势雄性，在前列腺和大脑组织中染料木黄酮通过提高记录基因活性超过 2 倍表现出显著的雄激素竞争活性。在完整雄性的肺或骨骼肌中没有观察带抗雄激素活性。在相同的实验条件下小鼠前列腺的基因表达谱揭示，在前列腺中染料木黄酮以类似于记录小鼠的方式通过荧光素酶表达调节依赖雄激素的转录程序。结论，金雀异黄素在一些但不是所有的老鼠组织中是一种局部雄激素受体激动剂/拮抗剂，可以被视为一种组织特异性 AR 调制器。