Disposition of Flavanoids via Enteric Recycling

说明(申请人提供)：膳食类黄酮包括广泛的化合物，已被证明对健康有多种益处(例如，抗氧化剂、抗骨病)。抗癌和抗衰老)，这使它们在疾病预防和阻止人类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。我们研究的长期目标是确定肠道循环(刘和胡)。2002)有助于黄酮类化合物在人类体内的总体处置和生物活性。本研究的一般假设是，抑制肠道转运体介导的结合代谢产物的外流比抑制肠道结合酶更有效地减少黄酮类代谢物的腔内排泄，提高母体黄酮类化合物的局部、门脉和全身生物利用度。其具体目的是：(1)在使用选定的黄酮类化合物的各种已建立的模型中，确定是否肠道代谢和随后的代谢物的排泄比肝脏的代谢和排泄更重要；(2)使用RNA干扰或RNAi(例如，siRNA)和化学抑制剂来确定负责亲水性黄酮类结合物外流的主要外流转运体，以及细胞排泄亲水性黄酮类结合物的限速步骤；(3)确定沉默负责相关代表性黄酮类的代谢的主要异构体UDP-葡萄糖醛酸基转移酶或磺基转移酶如何改变Caco-2模型中黄酮类结合物的细胞排泄；以及(4)使用动力学方法确定能够降低外排转运体活性而不影响UGT或SULT活性或反之亦然的化学抑制剂，并确定主要外排转运体的抑制剂是否比主要结合酶的抑制剂在提高所选黄酮类化合物的局部、门脉和全身生物利用度方面更有效。通过这些研究，我们将进一步了解控制黄酮类化合物口服后命运的机制，并阐明黄酮类化合物口服生物利用度低的原因。这些发现可能被用来理解黄酮类化合物的作用机制，并设计出提高其在人体内的生物利用度的方法。

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.