The Effect of Phytochemicals on Biochemical Mechanisms R

植物化学物质对生化机制的影响 R

• 批准号: 6761402
• 负责人: GRACE YEH
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6761402
• 关键词: MCF7 cell; P glycoprotein; aromatic hydrocarbon receptor; benzanthracenes; benzopyrenes; cancer prevention; carcinogenesis inhibitor; chemical carcinogen; chemoprevention; flavonoids; nutrient interaction; nutrition aspect of cancer; nutrition related tag; toxin metabolism

Numerous lines of evidence have shown that diets rich in Numerous lines of evidence have shown that diets rich in fruits and vegetables prevent or slow various types of cancers, including breast, prostate, and kidney cancers. However, the plant constituents (phytochemicals) responsible for this, and their mechanisms of action, remain to be elucidated. In this, the major project of the Section, we have examined the effect of a number of phytochemicals on various biochemical mechanisms relevant to carcinogenesis. The phytochemicals studied include the flavonoids, which are present in all fruits and vegetables. These include diosmin, from citrus fruit, quercetin, the most abundant flavonoid which is present in all dietary plants, and galangin and kaempferol, metabolites of quercetin. Other phytochemicals include the b-diketones curcumin and dibenzoylmethane, and resveratrol, a phytoalexin present in grape skins and therefore in grape juice and wine. All of these compounds have been shown to be chemopreventive in animal models of cancer, and epidemiologic studies have shown that food items containing large amounts of these compounds are associated with a reduced risk of cancer. There are many biochemical and molecular events associated with the development of cancer. One of the most important pathways is mediated by the aryl hydrocarbon receptor (AhR). The AhR is a cytoplasmic transcription factor which, upon ligand binding, translocates to the nucleus, where, with its protein partner ARNT, it interacts with the xenobiotic responsive element (XRE) present in the promoter region of a number of genes. The best characterized molecular response to ligands of the AhR is the induction of expression of cytochrome P450 1A1 (CYP1A1). CYP1A1 is a Phase 1 metabolic enzyme which activates environmental procarcinogens to their ultimate genotoxic forms. In addition to CYP1A1, the AhR controls a number of other genes, termed the "AhR battery", which affect both the activation and detoxification of carcinogens. We have concentrated on the Phase 1, or activating, enzymes, including CYP1A1, CYP1B1, and CYP1A2. We have also examined the effect phytochemicals on quinone reductase, a Phase 2, or detoxifying, enzyme, that is part of the AhR battery. In carrying out this research, we have done both in vitro experimentation in a variety of cell lines, as well as in vivo experimentation in rodents. We have examined how certain phytochemicals affect the activity of the AhR, including its ability to bind carcinogenic ligands and to interact with the XRE. We have examined the transcriptional activation of CYP1A1 and determined the effect of chemopreventive compounds on the expression and enzymatic activity of CYP1A1, CYP1B1, and CYP1A2. We have studied a number of environmental carcinogens which bind to the AhR, such as benzo[a]pyrene (BP), a polycyclic aromatic hydrocarbon (PAH) that is a potent environmental carcinogen present in cooked meat, cigarettes, and as by-products of industrial waste. We have also examined 2,3,5,7-tetrachlorodibenzo-p-dioxin(TCDD), a member of the dioxin family of potent carcinogens and the prototypical AhR ligand. We have found that many dietary phytochemicals modulate the cellular response to environmental carcinogens by affecting the AhR. For example, we demonstrated that resveratrol inhibits both the activity and expression of CYP1A1 that is normally induced by carcinogens such as TCDD or BP. It does this by blocking the binding of the ligand-activated AhR with the XRE of the CYP1A1 promoter, preventing the up-regulation of transcription. In addition, it directly inhibits enzymatic activity by a competitive mechanism. Thus, this dual mechanism of inhibiting the major carcinogen activating enzyme in most tissues provides a biochemical mechanism for its proven chemopreventive effect. We have also found that AhR activity is modulated by curcumin, dibenzoylmethane, quercetin, diosmin, and a number of other phytochemicals. We are currently investigating the effect of these compounds on other mechanisms involved in carcinogenesis, including the modulation of expression of g-glutamyltranspeptidase and telomerase. In order to identify further molecular targets of phytochemicals, we are also utilizing microarray technology. We have also examined the effects of other chemopreventive compounds which are not phytochemicals, on the AhR. These include the steroid hormone dehydroepiandrosterone and the nonsteroidal anti-inflammatant drug, sulindac.

大量证据表明，富含水果和蔬菜的饮食可以预防或减缓各种癌症，包括乳腺癌、前列腺癌和肾癌。然而，负责这一点的植物成分（植物化学物质）及其作用机制仍有待阐明。在这一部分的主要项目中，我们研究了一些植物化学物质对与致癌作用有关的各种生化机制的影响。研究的植物化学物质包括黄酮类化合物，它存在于所有水果和蔬菜中。这些包括地奥司明，从柑橘类水果，槲皮素，最丰富的类黄酮，这是目前在所有的饮食植物，高良姜和山奈酚，槲皮素的代谢产物。其他植物化学物质包括b-二酮姜黄素和二苯甲酰甲烷，以及白藜芦醇，一种存在于葡萄皮中的植物抗毒素，因此也存在于葡萄汁和葡萄酒中。所有这些化合物都已在癌症动物模型中显示出化学预防作用，流行病学研究表明，含有大量这些化合物的食物与癌症风险降低有关。 有许多生物化学和分子事件与癌症的发展有关。最重要的途径之一是由芳香烃受体（AhR）介导的。AhR是一种细胞质转录因子，其在配体结合后易位至细胞核，在细胞核中，其与其蛋白质伴侣ARNT一起与存在于许多基因的启动子区中的异生素应答元件（XRE）相互作用。对AhR配体的最佳表征的分子反应是诱导细胞色素P450 1A 1（CYP 1A 1）的表达。CYP 1A 1是一种1相代谢酶，可将环境中的原致癌物活化为最终的遗传毒性形式。除了CYP 1A 1之外，AhR还控制许多其他基因，称为“AhR电池”，它们影响致癌物的活化和解毒。我们已经集中在第一阶段，或激活，酶，包括CYP 1A 1，CYP 1B 1和CYP 1A 2。我们还研究了植物化学物质对醌还原酶的影响，醌还原酶是一种2相或解毒酶，是AhR电池的一部分。在进行这项研究时，我们在各种细胞系中进行了体外实验，以及在啮齿动物中进行了体内实验。我们已经研究了某些植物化学物质如何影响AhR的活性，包括其结合致癌配体和与XRE相互作用的能力。我们研究了CYP 1A 1的转录激活，并确定了化学预防化合物对CYP 1A 1、CYP 1B 1和CYP 1A 2的表达和酶活性的影响。我们已经研究了一些与AhR结合的环境致癌物，如苯并[a]芘（BP），一种多环芳烃（PAH），是熟肉，香烟中存在的强效环境致癌物，并作为工业废物的副产品。我们还研究了2，3，5，7-四氯二苯并-p-二恶英（TCDD），二恶英家族的一个成员的强致癌物和原型AhR配体。我们已经发现，许多膳食植物化学物质调节细胞对环境致癌物的反应，通过影响AhR。例如，我们证明白藜芦醇抑制CYP 1A 1的活性和表达，而CYP 1A 1通常由致癌物如TCDD或BP诱导。它通过阻断配体激活的AhR与CYP 1A 1启动子的XRE的结合来实现这一点，从而阻止转录的上调。此外，它通过竞争机制直接抑制酶活性。因此，这种抑制大多数组织中主要致癌物活化酶的双重机制为其已证实的化学预防作用提供了生化机制。我们还发现AhR活性受到姜黄素、二苯甲酰基甲烷、槲皮素、地奥司明和许多其他植物化学物质的调节。我们目前正在研究这些化合物对致癌作用中其他机制的影响，包括对g-谷氨酰转肽酶和端粒酶表达的调节。为了进一步确定植物化学物质的分子靶点，我们还利用微阵列技术。我们还研究了其他化学预防化合物，不是植物化学物质，对AhR的影响。这些包括类固醇激素脱氢表雄酮和非甾体抗炎药舒林酸。