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.

Public Health Relevance

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 proposed study will identify means to improve the bioavailability of flavonoids and enhance the chance that flavonoids could be successfully developed into drugs. It is expected that significant advances achieved through this research are applicable to the development of other drugs with similar delivery challenges so we can develop more drugs for humans at an accelerated pace.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01GM070737-07A1
Application #
8697807
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Okita, Richard T
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Houston
Department
None
Type
Schools of Pharmacy
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77204
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Tang, Lan; Li, Ye; Chen, Wei-Ying et al. (2014) Breast cancer resistance protein-mediated efflux of luteolin glucuronides in HeLa cells overexpressing UDP-glucuronosyltransferase 1A9. Pharm Res 31:847-60
Gorla, Suresh Kumar; McNair, Nina N; Yang, Guangyi et al. (2014) Validation of IMP dehydrogenase inhibitors in a mouse model of cryptosporidiosis. Antimicrob Agents Chemother 58:1603-14
Liu, Wei; Kulkarni, Kaustubh; Hu, Ming (2013) Gender-dependent differences in uridine 5'-diphospho-glucuronosyltransferase have implications in metabolism and clearance of xenobiotics. Expert Opin Drug Metab Toxicol 9:1555-69
Wei, Yingjie; Wu, Baojian; Jiang, Wen et al. (2013) Revolving door action of breast cancer resistance protein (BCRP) facilitates or controls the efflux of flavone glucuronides from UGT1A9-overexpressing HeLa cells. Mol Pharm 10:1736-50
Xu, Beibei; Yang, Guanyi; Ge, Shufan et al. (2013) Validated LC-MS/MS method for the determination of 3-hydroxflavone and its glucuronide in blood and bioequivalent buffers: application to pharmacokinetic, absorption, and metabolism studies. J Pharm Biomed Anal 85:245-52
Ma, Guo; Wu, Baojian; Gao, Song et al. (2013) Mutual regioselective inhibition of human UGT1A1-mediated glucuronidation of four flavonoids. Mol Pharm 10:2891-903
Ye, Ling; Yang, Xiaoshan; Yang, Zhen et al. (2013) The role of efflux transporters on the transport of highly toxic aconitine, mesaconitine, hypaconitine, and their hydrolysates, as determined in cultured Caco-2 and transfected MDCKII cells. Toxicol Lett 216:86-99
Jiang, Wen; Xu, Beibei; Wu, Baojian et al. (2012) UDP-glucuronosyltransferase (UGT) 1A9-overexpressing HeLa cells is an appropriate tool to delineate the kinetic interplay between breast cancer resistance protein (BRCP) and UGT and to rapidly identify the glucuronide substrates of BCRP. Drug Metab Dispos 40:336-45
Wu, Baojian; Wang, Xiaoqiang; Zhang, Shuxing et al. (2012) Accurate prediction of glucuronidation of structurally diverse phenolics by human UGT1A9 using combined experimental and in silico approaches. Pharm Res 29:1544-61

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