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

• 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
• 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

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（由申请人提供）：饮食中的类黄酮具有广泛的生物学作用，包括抗癌，抗氧化剂，抗抑制性，抗抑制性，降低胆固醇和抗衰老，这使它们在预防癌症和心血管疾病以及阻碍退行性疾病的进展方面具有吸引力。但是，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发展。我们研究的长期目标是确定亲水性II期偶联的外排转运蛋白如何控制类黄酮的总体处置并确定其在体内的生物命运。本研究建议的中心假设是类黄酮的局部和系统性生物利用度将是 通过调节负责其分布蛋白对局部靶器官（例如结肠）或全身循环的关键外排转运蛋白的功能进行改进。我们的中心假设超出了经典假设的一步，即只有在吸收更多和/或更少的吸收量的代谢时才能改善药物的生物可用性。该更新建议的具体目的是：（1）构建精确的定量细胞代谢模型，以描述分子水平上葡萄糖醛酸形成和外排的动力学； （2）确定针对黄酮类葡萄糖醛酸的三个关键外排转运蛋白的定量结构效能关系（QSER）：BCRP，MRP2和MRP3； （3）建立一个葡萄糖醛酸化分类系统，以绘制哪种类黄酮可以通过操纵特定的外排运输蛋白来具有良好的生物利用度。成功完成我们的研究项目将大大提高基本科学以及可用于改善类黄酮和人类健康相关药物的生物利用度的实践知识。

项目成果

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

Understanding substrate selectivity of human UDP-glucuronosyltransferases through QSAR modeling and analysis of homologous enzymes.

• DOI: 10.3109/00498254.2012.663515
• 发表时间: 2012-08
• 期刊: Xenobiotica; the fate of foreign compounds in biological systems
• 作者: Dong D;Ako R;Hu M;Wu B
• 通讯作者: Wu B

A new strategy to rapidly evaluate kinetics of glucuronide efflux by breast cancer resistance protein (BCRP/ABCG2).

• DOI: 10.1007/s11095-012-0817-2
• 发表时间: 2012-11
• 期刊: PHARMACEUTICAL RESEARCH
• 影响因子: 3.7
• 作者: Wu, Baojian;Jiang, Wen;Yin, Taijun;Gao, Song;Hu, Ming
• 通讯作者: Hu, Ming

Regioselective glucuronidation of flavonols by six human UGT1A isoforms.

• DOI: 10.1007/s11095-011-0418-5
• 发表时间: 2011-08
• 期刊: PHARMACEUTICAL RESEARCH
• 影响因子: 3.7
• 作者: Wu, Baojian;Xu, Beibei;Hu, Ming
• 通讯作者: Hu, Ming

Evaluation of 3,3',4'-trihydroxyflavone and 3,6,4'-trihydroxyflavone (4'-O-glucuronidation) as the in vitro functional markers for hepatic UGT1A1.

• DOI: 10.1021/mp200300w
• 发表时间: 2011-12-05
• 期刊: Molecular pharmaceutics
• 影响因子: 4.9
• 作者: Wu B;Zhang S;Hu M
• 通讯作者: Hu M