Absorption and Metabolism of Isoflavones

说明(申请人提供)：染料木素是一种异黄酮类植物雌激素，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。染料木素以大豆异黄酮类补充剂的形式被普通公众广泛食用。尽管金雀异黄素和其他异黄酮已被证明具有体外抗癌活性，但其生物利用度较低。此外，母体化合物或其代谢物之一是否是活性物种还没有仔细确定。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，染料木素的体内浓度(在NM范围内)远远低于在体外(在MU范围内)显示抗癌活性所需的浓度。因此，我们研究的长期目标是增加我们对异黄酮类(和其他植物雌激素)在肠道中的分布的了解，以便我们能够提高活性物种的生物利用度，确保它们作为化学预防药物的安全和有效使用。在本方案中，我们将通过体外、原位和体内模型来研究异黄酮类及其结合物在肠道中的吸收/排泄途径，并确定肠道处置如何影响异黄酮类化合物在体内的生物转化和生物利用度。本研究的目的被缩写为：(1)确定糖苷的区域依赖性(即十二指肠、空肠、回肠和结肠)水解性；(2)确定葡萄糖转运体在糖苷跨皮转运中的作用；(3)确定糖苷在肠道中外流的生物学基础；(4)鉴定负责异黄酮类化合物肠道代谢的UGT异构体(S)，并确定负责UGT结合物肠道分泌的外排机制；以及(5)确定肠道处置过程将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。这些拟议的研究将解释哪些机制导致这类植物雌激素的生物利用度较低。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(通过操纵肠道吸收和生物转化)是否将转化为更高的疗效。这种药效研究有助于确定对观察到的抗癌活性负责的活性物种，这对于理解异黄酮类化合物的作用机制非常重要。

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.