SOY ISOFLAVONE METABOLITE EQUOL

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。雌马酚是一种非甾体类雌激素，是摄入的大豆异黄酮的最重要代谢产物。它是由来自大豆黄酮的肠道细菌制成的，在4个月之前的婴儿的尿液和血液中没有发现。由于未知的原因，大豆黄酮转化为雌马酚在食用大豆食品的成年人中是可变的，似乎与饮食有关。最近对骨质疏松症预防、心血管健康和更年期的研究表明，与那些不能制造雌马酚的人相比，大豆食品对“雌马酚生产者”的有益影响要大得多，现在人们意识到，这两个不同的人群需要在饮食干预研究中进行定义。雌马酚以两种对映体形式存在，R-雌马酚和S-雌马酚，我们已经表明S-雌马酚对雌激素受体ER-β具有高亲和力，并显示与ER-α的结合可忽略不计。另一方面，R-雌马酚具有有效的抗雄激素特性，拮抗双氢睾酮的作用，使其具有药理学意义。将首次测定S-和R-雌马酚的药代动力学。我们的目的是证明，S-雌马酚发生在人体血浆和尿液中，不是因为两种对映体的吸收差异，而是由于细菌对映体特异性形成。由于有优势，是一个雌马酚生产者，重要的是要了解的因素，管理雌马酚生产。 我们将确定雌马酚何时首次出现在生命早期，以及是否是早期婴儿营养类型的差异，或断奶后饮食的组成使雌马酚易于产生（目标1）。与奶瓶喂养相比，母乳喂养导致肠道细菌定植的差异和较低的pH值，预计这将促进雌马酚的形成。初步的体外和人体数据表明，某些益生元大量营养素的摄入量较高，有利于结肠发酵，有利于雌马酚的形成。这将通过比较健康成年人的雌马酚产生量与其大量营养素饮食摄入量来确定，使用从食物频率问卷和3天饮食记录确定的纤维摄入量来分层组（目标2）。我们将确定雌马酚在成人中的长期稳定性及其对抗生素使用的反应（目标3）。此外，我们将确定R-雌马酚和S-雌马酚在接受单次口服推注剂量的受试者中的代谢和药代动力学（目的4）。考虑到雌马酚的临床相关性，对其生产因素的更深入了解将有助于未来控制雌马酚生产和提高大豆食品整体临床有效性的策略。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Equol, a non-steroidal estrogen of the isoflavone class, is the most important metabolite of ingested soy isoflavones. It is made by intestinal bacteria from the isoflavone daidzein, and not found in the urine and blood of infants before 4-months of age. For unknown reasons daidzein's conversion to equol is variable in adults consuming soy foods and seems diet related. Recent studies of osteoporosis prevention, cardiovascular health, and menopause have shown that beneficial effects from soy foods are significantly greater in people who are 'equol-producers' compared with those unable to make equol, and it is now realized that these two distinct populations need defining in dietary intervention studies. Equol exists in two enantiomeric forms, R-equol and S-equol, and we have shown that S-equol has a high affinity for estrogen receptor ER-beta and shows negligible binding to ER-alpha. R-equol on the other-hand has potent anti-androgen properties, antagonizing the actions of dihydrotestosterone, making it of pharmacological interest. For the first time, the pharmacokinetics of S- and R-equol will be determined. Our aim is to prove that S-equol occurs in human plasma and urine not because of differences in the absorption of the two enantiomers, but due to bacterial enantiomeric-specific formation. Since there are advantages to being an equol-producer it is important to understand the factors governing equol production. We will determine when equol first appears in early life and whether it is differences in the type of early infant nutrition, or the composition of the post-weaning diet that predispose to the production of equol (Aim 1). Breast-feeding leads to differences in intestinal bacterial colonization and a lower pH compared with bottle-feeding, and this is expected to facilitate equol formation. Preliminary in vitro and human data suggest higher intakes of certain prebiotic macronutrients conducive to colonic fermentation favor equol formation. This will be determined by comparing equol-production in healthy adults relative to their dietary intakes of macronutrients using fiber intake determined from food frequency questionnaire and 3-day diet records to stratify groups (Aim 2). We will determine the long-term stability of equol-production in adults and its response to antibiotic use (Aim 3). Also, we will determine the metabolism and pharmacokinetics of R-equol and S-equol in subjects taking a single oral bolus dose (Aim 4). Given the clinical relevance of equol, a greater understanding of factors governing its production will facilitate future strategies to manipulate equol production and enhance the overall clinical effectiveness of soy foods.