Disposition of Flavonoids via Glucuronidation, Critical Role of Efflux Transporte

说明(申请人提供)：膳食中的黄酮类化合物具有广泛的生物学作用，包括抗癌、抗氧化、抗骨质疏松症、降低胆固醇和抗衰老，使其在预防癌症和心血管疾病以及阻止退行性疾病的进展方面具有吸引力。然而，这些化合物的生物利用度很低，这阻碍了它们作为可行药物的开发。我们研究的长期目标是确定亲水性II相结合物的外排转运体如何控制类黄酮类化合物的整体处置，并决定它们在体内的生物命运。目前研究建议的中心假设是，黄酮类化合物的局部和全身生物利用度将是 通过调节负责将其分配到局部靶器官(例如，结肠)或体循环的关键外流转运体的功能而得到改善。我们的中心假说超越了经典假说，即只有当更多的药物被吸收和/或更少的吸收量被代谢时，药物的生物利用度才能提高。这项更新建议的具体目标是：(1)构建精确的定量细胞代谢模型，在分子水平上描述葡萄糖醛酸苷的形成和外排动力学；(2)确定黄酮类葡萄糖醛酸苷的三个关键外排转运体：BCRP、MRP2和MRP3的定量结构-外流关系(QSERs)；以及(3)建立葡萄糖醛酸化分类系统，通过操纵特定的外排转运体来绘制哪种黄酮类化合物可能具有良好的生物利用度。我们的研究项目的成功完成将极大地促进基础科学和实用知识的发展，这些知识可用于提高类黄酮和相关药物对人类健康的生物利用度。

DESCRIPTION (provided by applicant): Dietary flavonoids exert a broad range of biological effects including anticancer, antioxidant, antiosteoperosis, cholesterol lowering, and anti-aging, which make them attractive for preventing cancer and cardiovascular ailments and for impeding the progress of degenerative diseases. However, these compounds are poorly bioavailable, which impedes their development as viable drugs. The long-term goal of our study is to determine how efflux transporters of hydrophilic phase II conjugates control the overall disposition of flavonoids and determine their biological fate in vivo. The central hypothesis for the present research proposal is that the local and systemic bioavailability of a flavonoid will be improved by modulating the function of a critical efflux transporter responsible for its distributin to the local target organs (e.g., colon) or the systemic circulation. Our central hypothesis is a step beyond the classical hypothesis that bioavailabilities of drugs can only be improved if more are absorbed and/or less of the absorbed amount is metabolized. The Specific Aims of this renewal proposal are to: (1) construct precise quantitative cellular metabolic models to describe the kinetics of glucuronide formation and efflux at the molecular level; (2) determine the quantitative structure-efflux relationships (QSERs) for three key efflux transporters of flavonoid glucuronides: BCRP, MRP2, and MRP3; and (3) establish a glucuronidation classification system to map which flavonoid is likely to have good bioavailability by manipulating a particular efflux transporter. Successful completion of our research project will significantly advance the basic sciences as well as practical knowledge that may be used to improve the bioavailability of flavonoids and relevant drugs for human health.