Mechanisms for Benzo(a)pyrene-Induced Colon Cancer Exacerbation by Dietary Fat

膳食脂肪导致苯并(a)芘诱发结肠癌恶化的机制

基本信息

批准号：
8403767
负责人：
Aramandla Ramesh
金额：
$ 27.72万
依托单位：
MEHARRY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-10 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8403767
关键词：
8-Oxo-2&apos -Deoxyguanosine Adult Affect Air Animal Model Aromatic Polycyclic Hydrocarbons Atherosclerosis Benzo(a)pyrene Biological Availability Biological Models CYP1A1 gene Cancer Etiology Carcinoma Cessation of life Charcoal Chemicals Chemoprevention Colon Colon Carcinoma Colorectal Cancer Colorectal Neoplasms Consumption Control Animal Cytochrome P450 DNA DNA Adduction DNA Adducts DNA Damage DNA Repair Data Developing Countries Development Diet Dietary Fats Dietary Intervention Dose Drug Kinetics Enzymes Epithelial Epoxide hydrolase Epoxy Compounds Etiology Event Exposure to F2-Isoprostanes Family Fatty acid glycerol esters Food Generations Genomics Glutathione Glycols Goals Health Hepatic Human Incidence Individual Intake Intestines Isoprostanes Laboratories Length Life Style Link Lipid Peroxidation Lipids Liver Location Malignant Neoplasms Measures Meat Mediating Metabolic Biotransformation Metabolic Pathway Metabolism Modeling Mucous Membrane Mus Mutation Obesity Oncogenes Oral Organ Oxidative Stress Pathway interactions Pharmaceutical Preparations Polyps Prevention strategy Production Property Quinones Recommendation Risk Role Secondary to Small Intestines Smoking Surveys Testing Time Tissues Toxic Environmental Substances Translating Unsaturated Fats Variant Western World Work absorption adduct adenoma base benzo(a)pyrene-DNA adduct body system carcinogenesis colon carcinogenesis cooking food consumption genotoxicity indexing jejunum mouse model novel oxidative damage prevent saturated fat tumor

项目摘要

PROJECT SUMMARY Benzo(a)pyrene [B(a)P] is a lipophilic environmental toxicant that is widely distributed in foods and air. This chemical is known to cause cancer in various organ systems. Our preliminary studies have shown that dietary exposure of mice to B(a)P via saturated fat results in an increased incidence of polyps in colon, some of which were invasive compared to mice that received B(a)P through unsaturated fat. Exposure of mice to B(a)P through saturated fat causes induction of cytochrome P450 family of enzymes resulting in an increased concentration of reactive metabolites, compared to those that received B(a)P through unsaturated fat. Similarly, exposure of mice to B(a)P via saturated fat also contributed to oxidative stress in mouse colon, shown by an increased concentration of F2-isoprostanes (markers of oxidative stress) in mouse colon. Our central hypothesis is that dietary fat enhances B(a)P-induced colon carcinogenesis through enhanced bioavailability of B(a)P, and possibly a greater accumulation of B(a)P in tissues, and greater levels of B(a)P metabolites. A linked hypothesis is that B(a)P effects are secondary to production of epoxide or quinones some of which form DNA adducts that cause genotoxicity. We will test our hypothesis by studying the effects of oral exposure of adult ApcMin mice to B(a)P in saturated versus unsaturated fat via the following specific aims: 1. Characterize the potentiating effect of saturated vs. unsaturated dietary fat on B(a)P-induced adenomas and carcinomas in the small intestine and colon of the ApcMin mouse; 2. Assess the impact of the type of dietary fat on B(a)P-induced expression of biotransformation enzymes, their activities and disposition of B(a)P metabolites in the ApcMin mouse; 3. Test whether B(a)P- induced colon cancer is mediated via epoxide- (genomic DNA adducts) or quinone (quinone, 8-oxo-dG and etheno adduct) pathways, or both, in the ApcMin mouse. Relevance of this project to human health Every year 56,000 deaths are attributed to colorectal cancer (CRC) in USA and in a great majority of the cases surveyed; consumption of well-done red meat and other saturated fats, rich in B(a)P were implicated as a possible causative factor. Our approach is novel in that it uses a mouse model system that replicates a human CRC scenario. Another novel aspect of our proposal is that it will evaluate the role of B(a)P metabolic pathway- specific biotransformation events in the causation of CRC. Our findings will serve as a prelude to conducting chemoprevention studies for CRC and help to synthesize drugs to prevent or delay the onset of colon cancer.

项目摘要苯并（a）pyrene [b（a）p]是一种亲脂环境有毒物，广泛分布在食品和空气中。这已知化学物质会在各种器官系统中引起癌症。我们的初步研究表明饮食通过饱和脂肪暴露于B（a）P导致结肠息肉的发生率增加，其中一些与通过不饱和脂肪接收B（a）P的小鼠相比，具有侵入性。小鼠暴露于b（a）p 通过饱和脂肪引起细胞色素P450酶家族的诱导，导致增加与不饱和脂肪接收B（a）P的反应性代谢物的浓度相比。同样，小鼠通过饱和脂肪暴露于b（a）p也有助于小鼠结肠中的氧化应激，通过小鼠结肠中F2-异前列腺（氧化应激的标志物）浓度增加所示。我们的中心假设是，饮食脂肪通过增强来增强B（a）P诱导的结肠癌发生 B（a）P的生物利用度，组织中B（a）p的积累可能更大，更高的水平 B（a）P代谢物。一个链接的假设是b（a）p效应继发于环氧化物的产生或奎因酮某些形成引起遗传毒性的DNA加合物。我们将通过研究成年APCMIN小鼠口腔暴露于饱和脂肪与不饱和脂肪中B（a）p的影响以下特定目的：1。表征饱和脂肪与不饱和饮食脂肪对的增强作用 B（a）在小鼠小肠和结肠中p（a）p诱导的腺瘤和癌； 2。评估饮食脂肪类型对B（a）P诱导的生物转化酶表达的影响，其活性和在APCMIN小鼠中b（a）p代谢产物的处置； 3。测试B（A）P诱导的结肠癌是否为通过环氧化物（基因组DNA加合物）或喹酮（奎因酮，8-氧和乙烯加合物）介导的途径，或两者都在Apcmin鼠标中。该项目与人类健康的相关性每年有56,000人死亡归因于美国的结直肠癌（CRC），在大多数情况下调查；食用良好的红肉和其他饱和脂肪，富含B（a）p的含量被认为是可能的病因因素。我们的方法是新颖的，因为它使用了复制人类的鼠标模型系统 CRC方案。我们提案的另一个新方面是，它将评估B（a）P代谢途径的作用 - CRC因果关系中的特定生物转化事件。我们的发现将成为进行进行的序幕 CRC的化学预防研究，并有助于合成药物以预防或延迟结肠癌的发作。