Intestinal Disposition of Chemoprevention Agents
化学预防剂的肠道处置
基本信息
- 批准号:6805153
- 负责人:
- 金额:$ 7.78万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2003
- 资助国家:美国
- 起止时间:2003-09-30 至 2006-08-31
- 项目状态:已结题
- 来源:
- 关键词:Cruciferaebiomarkercancer preventionchemopreventionenzyme activitygastrointestinal drug absorptiongastrointestinal nutrient absorptiongene expressionhigh performance liquid chromatographyisothiocyanateslaboratory ratliquid chromatography mass spectrometrymembrane permeabilitymembrane transport proteinsnutrition related tagpharmacokineticspolymerase chain reactionwestern blottings
项目摘要
DESCRIPTION (provided by applicant):
Dietary factors, particularly increased consumption of fruits and vegetables, can decrease the risk of developing cancer including gastrointestinal cancers among others. The presence of chemopreventive compounds in fruits and vegetables is believed to contribute to the role of diet in mitigating cancer risk. Many compounds with chemopreventive activity have been isolated from a host of edible plants (e.g., sulforaphane from broccoli and Brussels sprouts; resveratrol from grapes and peanuts; geraniol from lemongrass). These compounds provide a wealth of opportunity for the improvement of human health by decreasing the risk of developing cancer. However, the promise that a chemopreventive compound holds can only be realized if the compound has sufficient bioavailability to exert its pharmacological effect. For orally administered compounds (such as chemopreventive compounds from foods), intestinal disposition will play a major role in their overall bioavailability. While current research on chemopreventive compounds focuses on their discovery and discerning their mechanism of action, studies on the bioavailability and mechanisms of absorption and metabolism have been relatively lacking. Research on the intestinal disposition (i.e., intestinal permeability and metabolism) of chemopreventive agents is particularly important. The issue of intestinal disposition and how it affects bioavailability is critical to the in vivo biological activity of any orally ingested dietary compound. Sulforaphane (SFN), an isothiocyanate chemopreventive agent found in cruciferous vegetables, is known to modulate the expression of a membrane transport protein and several metabolizing enzymes that are present in the intestine. Therefore, to enhance our understanding of the oral bioavailability and mechanisms of absorption and metabolism of chemopreventive compounds, we propose to determine (A) the intestinal disposition of SFN and (B) how SFN's effects on gene/protein expression in the intestine (potential biomarkers of cancer chemoprevention activity) can affect the bioavailability of xenobiotics, including SFN itself. Our hypothesis is that dietary chemopreventive compounds such as SFN can affect their own bioavailability and the bioavailability of other xenobiotics by modulating the expression of Phase II detoxifying enzymes and membrane transporters in the Intestine. To test this hypothesis, the following Specific Aims will be addressed in this proposal:
Specific Aim 1: Determine the intestinal disposition of SFN in the rat using single-pass intestinal perfusion technique (SPIP) with and without mesenteric vein cannulation and diffusion chamber studies.
Specific Aim 2: Determine the effects of SFN on the gene expression of several Phase II detoxifying enzymes that are potential biomarkers of chemopreventive effects as well as membrane transporters that could affect intestinal disposition of xenobiotics and correlate the effects to the permeability of SFN.
Results from these studies will enhance our understanding of the bioavailability and mechanisms of absorption and metabolism of the dietary chemopreventive compound, SFN. The issues of intestinal disposition and bioavailability ultimately determine the in vivo effects of chemopreventive compounds and understanding the underlying mechanisms will lead to improved cancer prevention modalities.
描述(由申请人提供):
饮食因素,特别是增加水果和蔬菜的消费,可以降低患癌症的风险,包括胃肠道癌症等。水果和蔬菜中化学预防化合物的存在被认为有助于饮食在减轻癌症风险中的作用。许多具有化学预防活性的化合物已经从许多可食用植物中分离出来(例如,来自花椰菜和布鲁塞尔芽的萝卜硫素;来自葡萄和花生的白藜芦醇;来自柠檬草的香叶醇)。这些化合物通过降低患癌症的风险为改善人类健康提供了大量机会。然而,只有当化合物具有足够的生物利用度以发挥其药理作用时,才能实现化学预防化合物的前景。对于口服给药的化合物(如来自食物的化学预防化合物),肠道处置将在其总体生物利用度中发挥主要作用。虽然目前对化学预防化合物的研究集中在它们的发现和辨别它们的作用机制上,但对生物利用度以及吸收和代谢机制的研究相对缺乏。肠道处置研究(即,肠渗透性和代谢)是特别重要的。肠道处置及其如何影响生物利用度的问题对于任何口服摄入的膳食化合物的体内生物活性至关重要。萝卜硫素(SFN)是一种在十字花科蔬菜中发现的异硫氰酸酯化学预防剂,已知其调节存在于肠道中的膜转运蛋白和几种代谢酶的表达。因此,为了增强我们对化学预防化合物的口服生物利用度和吸收和代谢机制的理解,我们提出确定(A)SFN的肠处置和(B)SFN对肠中基因/蛋白质表达(癌症化学预防活性的潜在生物标志物)的作用如何影响外源性物质(包括SFN本身)的生物利用度。我们的假设是,膳食化学预防化合物,如SFN,可以通过调节肠道中II相解毒酶和膜转运蛋白的表达来影响其自身的生物利用度和其他外源性物质的生物利用度。为了检验这一假设,本提案将涉及以下具体目标:
具体目标1:采用单通道肠灌注技术(SPIP),在有和没有肠系膜静脉插管和扩散室研究的情况下,确定SFN在大鼠中的肠道分布。
具体目标二:确定SFN对几种II期解毒酶基因表达的影响,这些酶是化学预防效应的潜在生物标志物,以及可能影响外源性物质肠道处置的膜转运蛋白,并将这些效应与SFN的渗透性相关联。
这些研究的结果将加强我们对膳食化学预防化合物SFN的生物利用度和吸收代谢机制的理解。肠道处置和生物利用度的问题最终决定了化学预防化合物的体内作用,了解潜在的机制将导致改善癌症预防模式。
项目成果
期刊论文数量(0)
专著数量(0)
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