Absorption and Metabolism of Isoflavones

描述（由申请人提供）：染料木黄酮是一种异黄酮，是一种膳食植物雌激素，被认为具有化学预防作用，目前正在进行前列腺癌预防的临床试验。染料木黄酮以大豆异黄酮补充剂的形式被公众广泛食用。尽管染料木素和其他异黄酮已被证明具有体外抗癌活性，但其生物利用度较差。此外，母体化合物或其代谢物之一是否是活性物质尚未仔细确定。这是一个严重的问题，因为食用大豆食品或服用大豆异黄酮补充剂后获得的染料木素体内浓度（nM范围）远低于体外显示抗癌活性所需的浓度（muM范围）。因此，我们研究的长期目标是增加我们对异黄酮（和其他植物雌激素）的肠道处置的理解，以便我们可以提高活性物种的生物利用度，并确保它们作为化学预防剂的安全有效使用。在本研究中，我们将通过体外、原位和体内模型，重点研究异黄酮及其缀合物在肠道中的吸收/排泄途径，并确定肠道配置如何影响异黄酮在体内的生物转化和生物利用度。本研究的目的可以缩写为：(1)确定区域依赖性（即十二指肠、空肠、回肠和结肠）苷水解；(2)确定葡萄糖转运蛋白在糖苷经上皮转运中的作用；(3)明确肠内糖苷外排的生物学基础；(4)鉴定负责异黄酮肠道代谢的UGT异构体，确定负责UGT缀合物肠道分泌的外排机制；(5)确定肠道处置过程如何影响染料木素及其类似物的体内生物转化和生物利用度。这些拟议的研究将提供一个解释，哪些机制负责这类植物雌激素的低生物利用度。它们将构成未来疗效研究的基础，以确定改善的生物利用度（通过控制肠道吸收和生物转化）是否会转化为提高的疗效。这样的功效研究可以帮助鉴定具有观察到的抗癌活性的活性物质，对了解异黄酮的作用机制具有重要意义。

DESCRIPTION (provided by applicant): Genistein, an isoflavone, is a member of the dietary phytoestrogens that are believed to have chemopreventive effect and is currently undergoing clinical trial for prostate cancer prevention. Genistein is widely consumed by general public in the form of soy isoflavone supplements. Despite its proven in vitro anticancer activity, genistein and other isoflavones have poor bioavailability. In addition, whether the parent compound or one of its metabolites is the active species has not been carefully determined. This is a serious concern since the in vivo concentration of genistein achieved (in nM range) after soy food consumption or administration of soy isoflavone supplements are far lower than those necessary to show anticancer activity in vitro (in muM range). Therefore, the long-term goal of our study is to increase our understanding of the intestinal disposition of isoflavonoids (and other phytoestrogens) so that we can improve the bioavailability of active species and ensure their safe and effective use as chemopreventive agents. In the present proposal, we will focus our efforts on the study of absorption/excretion pathways of isoflavones and their conjugates in the intestine via the use of in vitro, in situ and in vivo models, and determine how intestinal disposition affects the biotransformation and bioavailability of isoflavonoids in vivo. The aims of this study are abbreviated as: (1) to determine region-dependent (i.e., duodenum, jejunum, ileum, and colon) hydrolysis of glycosides; (2) to determine the role played by glucose transporters in the transepithelial transport of glycosides; (3) to define the biological basis of glycoside efflux in the intestine; (4) to identify the UGT isoform(s) responsible for the intestinal metabolism of isoflavones and to determine the efflux mechanisms responsible for intestinal secretion of UGT conjugates; and (5) to determine how intestinal disposition processes will affect the in vivo biotransformation and bioavailability of genistein and its analogs. These proposed studies will provide an explanation as to which mechanisms are responsible for the poor bioavailability of this class of phytoestrogens. They will form the basis for future efficacy studies to determine if improved bioavailability (through manipulating intestinal absorption and biotransformation) will translate into increased efficacy. Such efficacy studies could help to identify the active species responsible for observed anticancer activities, important for the understanding of the mechanisms of action of isoflavones.