Disposition of Flavanoids via Enteric Recycling

通过肠道回收处理黄酮类化合物

• 批准号: 6969420
• 负责人: MING HU
• 金额: $ 14.2万
• 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 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6969420
• 关键词: RNA interference; cell line; chemical kinetics; chemical structure function; disease /disorder model; enzyme activity; excretion; flavonoids; gastrointestinal absorption /transport; glucuronosyltransferase; hydropathy; inhibitor /antagonist; laboratory mouse; laboratory rat; liver metabolism; oral administration; pharmacokinetics; protein isoforms; sulfotransferase; tissue /cell culture; uridine diphosphate

DESCRIPTION (provided by applicant): Dietary flavonoids include a broad range of compounds that have been shown to have a variety of health benefits (e.g., antioxidants, antiosteoperosis. anticancers, and anti-aging), which make them attractive for disease prevention and impeding the progress of degenerative diseases in humans. However, these compounds have poor bioavailabilities. The long-term goal of our study is to determine how enteric recycling (Liu and Hu. 2002) contributes to the overall disposition of flavonoids and to the biological activities of flavonoids in humans. The general hypothesis for the present research proposal is that the inhibition of intestinal transporter mediated efflux of conjugated metabolites is more effective than inhibition of intestinal conjugating enzymes in decreasing luminal excretion of flavonoid metabolites and in increasing, local, portal and systemic bioavailability of parent flavonoids. The specific aims are to: (1) determine if intestinal metabolism and subsequent excretion of metabolites is more important than liver metabolism and excretion in a variety of established models using selected flavonoids; (2) determine the main efflux transporters responsible for efflux of hydrophilic flavonoid conjugates using RNA interference or RNAi (e.g., siRNA) and chemical inhibitors, and the rate-limiting step in the cellular excretion of hydrophilic flavonoid conjugates; (3) determine how silencing of a main isoform of UDP-glucuronosyltransferase or sulfotransferases responsible for the metabolism of related representative flavonoids will change the cellular excretion of flavonoid conjugates in the Caco-2 model; and (4) identify chemical inhibitors that are capable of decreasing the efflux transporter activities without affecting the activities of UGT or SULT or vice versa using kinetic methods, and determine if inhibitors of main efflux transporter is more effective than inhibitors of the main conjugating enzyme in enhancing the local, portal and systemic bioavailabilities of selected flavonoids. Through these studies, we will further understand the mechanisms that control the fate of flavonoids following oral ingestion and shed light on the reasons why flavonoids have poor oral bioavailability. These findings may be used to understand the mechanisms of actions of flavonoids and to devise means of increasing their bioavailability in humans.

描述（由申请人提供）：饮食类黄酮包括各种各样的化合物，这些化合物已被证明具有多种健康益处（例如抗氧化剂，抗抑制性抗衰老，抗癌和抗衰老），使它们对预防疾病的吸引力，并促进了人类变性疾病的进展。但是，这些化合物的生物宽松度较差。我们研究的长期目标是确定肠回收（Liu andHu。2002）如何促进类黄酮的整体处置以及类黄酮在人类中的生物学活性。 本研究提案的一般假设是，抑制肠道转运蛋白介导的共轭代谢产物的外排比抑制肠道偶联酶在减少肠道上的介导酶排泄的抑制更为有效，而在降低了肠道，在降低肠道偶联的酶排泄量，并增加了肠道，在增加，局部和系统的，门户和系统的生物生物生物范围内的肠道代谢物。具体目的是：（1）确定使用选定的类黄酮的多种既定模型中的肠道代谢和随后的代谢排泄是否比肝脏代谢和排泄更为重要； （2）确定负责使用RNA干扰或RNAI（例如siRNA）和化学抑制剂的亲水性类黄酮偶联物外排的主要外排转运蛋白，以及在水亲核氟硅烷基偶联物的细胞排泄中的限制步骤； （3）确定如何使UDP-葡萄糖基转移酶的主要同工型或负责负责相关代表性黄酮代谢的磺胺转移酶进行沉默，将改变CACO-2模型中类黄酮偶联物的细胞排泄； （4）确定能够降低外流转运蛋白活性的化学抑制剂，而不会影响UGT或sult的活性，反之亦然，并确定主要外排转运蛋白的抑制剂是否比主要结合酶的抑制剂更有效，在增强本地酶的主要酶和选择性的Biobiobiobiobiobioavonabories flavonabianss和全身性薄膜上。通过这些研究，我们将进一步了解口服摄入后类黄酮的命运的机制，并阐明了类黄酮口服生物利用度较差的原因。这些发现可用于了解类黄酮的作用机制，并设计出增加其人类生物利用度的手段。