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，富含大量证据的饮食表明，富含水果和蔬菜的饮食预防或减慢各种类型的癌症，包括乳腺癌，前列腺和肾脏癌。然而，负责此的植物成分（植物化学物质）及其作用机理仍有待阐明。在本节的主要项目中，我们研究了许多植物化学物质对与癌变有关的各种生化机制的影响。研究的植物化学物质包括所有水果和蔬菜中都存在的类黄酮。其中包括diosmin，来自柑橘类水果，槲皮素，所有饮食植物中最丰富的类黄酮，以及槲皮素的Galangin和Kaempferol，Galangin和Kaempferol。其他植物化学物质包括B-黎酮姜黄素和二苯甲酰甲烷，以及白藜芦醇，白藜芦醇是葡萄皮中存在的植物甲状腺素，因此在葡萄汁和葡萄酒中。所有这些化合物在癌症的动物模型中都被证明是化学预防，并且流行病学研究表明，含有大量这些化合物的食品与癌症风险降低有关。 与癌症发展有关的许多生化和分子事件。最重要的途径之一是由芳基烃受体（AHR）介导的。 AHR是一种细胞质转录因子，在配体结合后，它易位到细胞核，其中及其蛋白伴侣ARNT与存在许多基因的启动子区域中的异种生物响应元件（XRE）相互作用。对AHR配体的分子反应的最佳特征是诱导细胞色素P450 1A1（CYP1A1）的表达。 CYP1A1是一种1期代谢酶，它将环境促骨毒素激活其最终的遗传毒性形式。除CYP1A1外，AHR还控制了许多其他基因，称为“ AHR电池”，这会影响致癌物的激活和排毒。我们集中在第1阶段，或激活的酶，包括CYP1A1，CYP1B1和CYP1A2。我们还研究了植物化学对喹酮还原酶的效果，A阶段2或排毒酶，即AHR电池的一部分。在进行这项研究时，我们在多种细胞系和啮齿动物的体内实验中进行了体外实验。我们已经检查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。我们已经检查了CYP1A1的转录激活，并确定了化学预防化合物对CYP1A1，CYP1B1和CYP1A2的表达和酶活性的影响。我们已经研究了许多与AHR结合的环境致癌物，例如苯并[A] pyrene（BP），这是一种多环芳族烃（PAH），是一种有效的环境致癌物，存在于煮熟的肉，香烟中，以及作为工业废物的副产品。我们还检查了2,3,5,7-四氯二苯甲酸-P-二恶英（TCDD），这是二恶英家族的有效致癌物和原型AHR配体的成员。我们发现，许多饮食植物化学物质通过影响AHR来调节细胞对环境致癌物的反应。例如，我们证明白藜芦醇抑制了通常由TCDD或BP等致癌物诱导的CYP1A1的活性和表达。它通过阻止了配体激活的AHR与CYP1A1启动子的XRE的结合，从而阻止了转录的上调。另外，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酶的双重机制为其证明的化学预防作用提供了生化机制。我们还发现，AHR活性是由姜黄素，二苯甲酰甲烷，槲皮素，二敏和许多其他植物化学物质调节的。我们目前正在研究这些化合物对癌变涉及的其他机制的影响，包括调节G-谷氨酰基肽酶和端粒酶的表达。为了确定植物化学物质的进一步分子靶标，我们还利用微阵列技术。我们还研究了非植物化学物质对AHR的其他化学预防化合物的作用。其中包括类固醇激素脱氢表甲酮酮和非甾体类抗炎药Sulindac。