Disposition of Flavonoids via Glucuronidation, Critical Role of Efflux Transporte

通过葡萄糖醛酸化处理黄酮类化合物，外排转运的关键作用

基本信息

批准号：
9267482
负责人：
MING HU
金额：
$ 52.66万
依托单位：
UNIVERSITY OF HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-06-05 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9267482
关键词：
ABCG2 gene Animal Model Antioxidants Basic Science Beta-glucuronidase Bioavailable Biological Biological Availability Blood Circulation Cardiovascular system Cell model Cholesterol Classification Colon Complex Degenerative Disorder Development Dietary Flavonoid Drug Compounding Drug Design Drug Kinetics Effectiveness Enteral Enzymes Flavonoids Genistein Glucuronides Glucuronosyltransferase Goals Health Health Benefit Human Hydrolysis In Vitro Intestinal Absorption Kinetics Knowledge Malignant Neoplasms Maps Mathematics Metabolic Metabolic Pathway Metabolism Modeling Molecular Mus Organ Pharmaceutical Preparations Phase Process Production Protein Isoforms Recycling Research Research Project Grants Research Proposals Role Safety Science Structure System Testing Time Tissues UGT1A1 gene Unspecified or Sulfate Ion Sulfates Validation anti aging design enzyme activity hydrophilicity improved in vivo inhibitor/antagonist innovation mathematical model overexpression practical application prevent public health relevance sulfotransferase

项目摘要

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.

描述（申请人提供）：膳食类黄酮具有广泛的生物效应，包括抗癌、抗氧化、抗骨质疏松、降低胆固醇和抗衰老，这使得它们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较差，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 相缀合物的外排转运蛋白如何控制类黄酮的整体分布并确定它们在体内的生物命运。本研究计划的中心假设是类黄酮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）或全身循环的关键外排转运蛋白的功能来改善。我们的中心假设超越了经典假设，即只有更多的药物被吸收和/或更少的吸收量被代谢，药物的生物利用度才能提高。该更新提案的具体目标是：（1）构建精确的定量细胞代谢模型，以在分子水平上描述葡萄糖苷酸形成和流出的动力学； (2) 确定类黄酮葡萄糖苷酸的三个关键外排转运蛋白的定量结构-外排关系 (QSER)：BCRP、MRP2 和 MRP3； (3) 建立葡萄糖醛酸化分类系统，通过操纵特定的外排转运蛋白来绘制哪些类黄酮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推进基础科学和实践知识的发展，这些知识可用于提高黄酮类化合物和相关药物对人类健康的生物利用度。

项目成果

期刊论文数量（81）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Glucuronidation: driving factors and their impact on glucuronide disposition.

DOI：
10.1080/03602532.2017.1293682
发表时间：
2017-05
期刊：
Drug metabolism reviews
影响因子：
5.9
作者：
Yang G;Ge S;Singh R;Basu S;Shatzer K;Zen M;Liu J;Tu Y;Zhang C;Wei J;Shi J;Zhu L;Liu Z;Wang Y;Gao S;Hu M
通讯作者：
Hu M

Regioselective glucuronidation of flavonols by six human UGT1A isoforms.