Absorption and Metabolism of Isoflavones

描述（由申请人提供）：染料木黄酮是一种植物雌激素，被认为是具有化学预防作用的膳食植物雌激素的一员，目前正在进行预防前列腺癌的临床试验。染料木黄酮以大豆蛋白补充剂的形式被公众广泛消费。尽管其体外抗癌活性已被证实，但染料木黄酮和其他黄酮类化合物的生物利用度很差。此外，尚未仔细确定母体化合物或其代谢产物之一是否为活性物质。这是一个严重的问题，因为在食用大豆食品或给予大豆黄酮补充剂后，染料木黄酮的体内浓度（nM范围）远低于体外显示抗癌活性所需的浓度（μ M范围）。因此，我们研究的长期目标是增加我们对雌激素（和其他植物雌激素）的肠道分布的了解，以便我们可以提高活性物质的生物利用度，并确保它们作为化学预防剂的安全有效使用。在本提案中，我们将集中我们的努力，通过使用在体外，原位和体内模型的吸收/排泄途径的研究，并确定肠道处置如何影响体内的生物转化和生物利用度的阿托伐他汀及其共轭物。本研究的目的简称为：（1）确定区域依赖性（即，十二指肠、空肠、回肠和结肠）水解糖苷;（2）确定葡萄糖转运蛋白在糖苷的跨上皮转运中所起的作用;（3）确定糖苷在肠中流出的生物学基础;（4）鉴定负责β-葡糖苷酮肠代谢的UGT同种型，并确定负责UGT缀合物肠分泌的流出机制;以及（5）确定肠处置过程将如何影响染料木黄酮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，哪些机制是负责这类植物雌激素的生物利用度差。它们将成为未来疗效研究的基础，以确定改善的生物利用度（通过操纵肠道吸收和生物转化）是否会转化为增加的疗效。这种功效研究可以帮助确定负责观察到的抗癌活性的活性物质，这对于理解马槟榔酮的作用机制很重要。

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.