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

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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.