A Molecular Basis for Phytoestrogen Chemoprevention

尽管雌激素替代疗法(ERT)在绝经后被证明对健康有好处，但目前只有30%的美国女性正在接受ERT，因为过度暴露于合成雌激素与子宫内膜、乳房、肾脏和肝脏等几个组织的癌症发展明显相关。因此，许多女性在饮食中寻求有效的、天然的、植物来源的(植物)雌激素替代品，以便她们可以保持雌激素的有益特性，而不会受到遗传毒性影响。饮食中植物雌激素的两个主要来源是大豆和红三叶草，其次是甘草和啤酒花。大豆和红三叶中的四种主要植物雌激素化合物是异黄酮染料木素、大豆异黄素、木犀草素-A和芒柄花素。最近在甘草和啤酒花中发现的两种植物雌激素化合物是光滑菌素和8-戊烯基柚皮苷。通过体内和/或体外生物测定，所有这六个化合物都被证明具有雌激素样或抗雌激素样活性，或两者的混合物，取决于雌激素受体(ER)同工酶，α或β，是靶点。通过比较染料木素与ER-β(迄今唯一的植物雌激素-ER-ER结构)、雌激素(激动剂)与ER-α结合的激动剂(激动剂)和雷洛昔芬(拮抗剂)与ER-β结合后的X射线结构，发现植物雌激素染料木素在ER中诱导了一种新的构象。这种构象既不是纯激动剂，也不是纯拮抗剂，而是一种介于两者之间的构象。这一结果提出了一种假设，即每种饮食中的植物雌激素都可以诱导ER-α和ER-β的独特构象，这可能会诱导一种类型的转导活性，从而在不诱导有害转录事件(即肿瘤细胞生长和/或增殖)的情况下，提供所需的雌激素样或抗雌激素样作用。因此，这项建议的具体目标是。)解决与上述六种植物雌激素络合的ER-α和ER-β的高分辨X射线结构。)构建定量构效关系(QSAR)，可用于先验预测新鉴定的植物雌激素化合物的生物活性，并有助于设计可作为选择性雌激素调节剂(SERM)的新化合物。

Despite the proven health benefits of estrogen replacement therapy (ERT) in their postmenopausal years, only 30% of women in the United States are currently receiving ERT because of a clear association between excessive exposure to synthetic estrogens and the development of cancer in several tissues including endometrium, breast, kidney and liver. As a result, many women are seeking effective and natural, plant- derived (phyto) estrogen replacement alternatives in their diet that so that they may maintain the beneficial properties of estrogens without receiving the genotoxic effects. Two of the major sources of dietary phytoestrogens are soy and red clover, and to a lesser extent licorice and hops. Four of the major phytoestrogen compounds in soy and red clover are the isoflavones genistein, daidzen, biochanin-A and formononetin. Two recently identified phytoestrogen compounds in licorice and hops are glabridin and 8-prenylnaringenin. All six of these compounds have been shown via in-vivo and/or in-vitro bioassays to have either estrogenic or anti-estrogenic activity, or a mixture of both depending on what estrogen receptor (ER) isozyme, alpha or beta, is being targeted. A comparison of the x-ray structure of genistein complexed with ER-beta, the only phytoestrogen-ER structure solved to date, to those of estradiol (agonist) bound to ER-alpha and Raloxifene (antagonist) bound to ER- beta, reveals that the phytoestrogen genistein induces a novel conformation in ER. This conformation is neither that of a pure agonist nor or a pure antagonist but is proposed to be a conformation in between. This result invokes the hypothesis that each of the dietary phytoestrogens may induce unique conformations in both ER-alpha and ER-beta that may induce the type of transciptional activity that gives desired estrogenic or anti-estrogenic effects without inducing harmful transcription events i.e. tumor cell growth and/or proliferation. The specific aims of this proposal are therefore to i.) solve the high resolution x-ray structures of ER-alpha and ER-beta complexed with the six phytoestrogens listed above and to ii.) construct a quantitative structure- activity relationship (QSAR) that can be used to predict a priori the biological activity of newly identified phytoestrogen compounds and to II.)aid in the design of new compounds that can serve as selective estrogen modulators (SERMs).