A Molecular Basis for Phytoestrogen Chemoprevention

尽管雌激素替代疗法（ERT）对绝经后妇女的健康有益，但目前在美国只有30%的妇女接受ERT，因为过度暴露于合成雌激素与子宫内膜、乳房、肾脏和肝脏等几种组织的癌症发展之间存在明确的关联。因此，许多妇女在饮食中寻求有效的、天然的、植物性的雌激素替代品，这样她们就可以保持雌激素的有益特性，而不会受到遗传毒性的影响。膳食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。大豆和红三叶草中的四种主要植物雌激素化合物是异黄酮染料木素、大黄酮、生物茶豆素a和刺芒柄花素。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甘草定和8-烯丙基柚皮苷。所有这六种化合物已通过体内和/或体外生物测定显示具有雌激素活性或抗雌激素活性，或两者的混合物，这取决于所针对的雌激素受体（ER）同工酶是α还是β。将染料木黄酮与ER- β络合的x射线结构（迄今为止唯一的植物雌激素-ER结构）与雌二醇（激动剂）与ER- α结合的x射线结构和雷洛昔芬（拮抗剂）与ER- β结合的x射线结构进行比较，发现植物雌激素染料木黄酮在ER- β中诱导了一种新的构象。这种构象既不是纯激动剂的构象，也不是纯拮抗剂的构象，而是介于两者之间的构象。这一结果提出了一种假设，即每一种膳食植物雌激素都可以诱导er - α和er - β的独特构象，从而诱导转录活性的类型，从而产生所需的雌激素或抗雌激素作用，而不会诱导有害的转录事件，即肿瘤细胞生长和/或增殖。因此，本研究的具体目标是：(1)解决er - α和er - β与上述六种植物雌激素络合的高分辨率x射线结构；(2)构建定量结构-活性关系（QSAR），可用于预测新鉴定的植物雌激素化合物的生物活性；(2)帮助设计可作为选择性雌激素调节剂（SERMs）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).