Impact of dietary fat and obesity on biotransformation, tissue distribution and bioactivity of isoflavones

异黄酮(IF)的生物利用度和复杂的生物转化在个体之间都是高度可变的，对它们的生物活性有很大的影响，从而影响临床和动物研究的结果。根据我们先前的发现，大约45%的IF及其代谢产物与血浆脂蛋白(LP)相关，我们推测LP可能是IF进入靶组织的重要载体。因此，影响循环Lp数量和组成的因素可能会影响If-Lp联结和If在Lp亚类内的分布。因此，如果生物利用度，如果组织浓度和最终的生物活性可能会改变。在这个项目中，我们将关注两个因素，这两个因素一方面影响血浆脂蛋白水平，另一方面与绝经后女性乳腺癌风险的增加有关：肥胖和高饮食脂肪摄入量。在一项针对绝经后妇女的短期和长期人类干预研究中，将回答以下问题：1)总体脂肪质量和/或高饮食脂肪摄入量是否会改变代谢和向目标组织的分布？2)脂蛋白的作用是什么？3)生物利用度和代谢的变化是否会改变乳腺癌和肥胖相关生物标志物的生物活性？4)如果饮食调节肥胖相关DNA甲基化的变化，是否有规律？为了更好地将动物研究移植到人类环境中，并表征物种(人/鼠)在生物利用度和生物转化方面的特定差异，将在与Wistar大鼠的可比研究中解决相同的问题。

The bioavailability and the complex biotransformation of isoflavones (IF), which are both highly variable among individuals, have a substantial impact on their biological activity and thus on outcomes from clinical as well as animal studies. Based on our previous finding that around 45% of IF and their metabolites are associated to plasma lipoproteins (LP), we postulate that LP might be important vectors for IF to access target tissues. Therefore, factors which influence the amount and composition of circulating LP might affect the IF-LP association and IF distribution within LP subclasses. As a consequence IF bioavailability, IF tissue concentration and in the end the biological activity could be altered. In this project, we will focus on two factors which on one hand have an impact on the plasma LP profile and on the other hand are associated with an increased breast cancer risk in postmenopausal women: obesity and high intake of dietary fat. In one short-term and one long-term human intervention study with postmenopausal women, the following questions will be answered: 1) Do total body fat mass and/or a high intake of dietary fat confer changes in IF metabolism and distribution to target tissues? 2) What is the role of the LP? 3) Do the variations in bioavailability and metabolism alter IF bioactivity on mammary cancer- and obesity-related biomarkers? 4) Does regular IF consumption modulate obesityrelated DNA-methylation changes? To allow better transferability of animal studies to the human situation, and to characterize species (human/rat) specific differences in the bioavailability and biotransformation the same questions will be addressed in comparable studies with Wistar rats.