Pilot Project: 3 "Dietary Fat Potentiation of B(a)P Induced Colon Cancer"

试点项目：3“膳食脂肪增强 B(a)P 诱发结肠癌”

• 批准号: 7650250
• 负责人: Aramandla Ramesh
• 金额: $ 10.25万
• 依托单位: MEHARRY MEDICAL COLLEGE
• 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/7650250
• 关键词: Address; Adult; Affect; Americas; Animal Model; Aromatic Polycyclic Hydrocarbons; Benzo(a)pyrene; Breast; CYP1A1 gene; Carcinogenesis Mechanism; Cessation of life; Characteristics; Chemicals; Chemoprevention; Chemopreventive Agent; Chemosensitization; Chronic; Colon; Colon Carcinoma; Colonic Neoplasms; Colorectal; Colorectal Cancer; Condition; Consumption; Cytochrome P450; DNA; DNA Adduction; DNA Damage; DNA Modification Process; Depth; Developed Countries; Developing Countries; Development; Diet; Dietary Fats; Dose; Drug Kinetics; End Point; Enzymes; Epoxide hydrolase; Epoxy Compounds; Etiology; Family; Fatty acid glycerol esters; Food; Generations; Genus Cola; Glutathione S-Transferase; Goals; Health; Histologic; Human; Ingestion; Intake; Investigation; Isoprostanes; Knowledge; Length; Life Style; Lipid Peroxidation; Lipids; Location; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Meat; Mediating; Metabolic Biotransformation; Metabolism; Mus; Numbers; Oral; Organ; Oxidative Stress; Pathway interactions; Pharmaceutical Preparations; Pilot Projects; Plasma; Poison; Pongidae; Population; Principal Investigator; Production; Prostate; Quinones; Range; Rattus; Risk; Role; Series; Severities; Small Intestines; Smoking; Stomach; Surveys; Testing; Time; Tissues; Toxic Environmental Substances; Toxic effect; Translating; United States; Unsaturated Fats; Variant; Western World; adduct; adenoma; base; benzo(a)pyrene-DNA adduct; benzoquinone; body system; carcinogenesis; colon carcinogenesis; cooking; day; dihydrodiol dehydrogenases; enzyme activity; indexing; insight; prevent; research study; saturated fat; size; trans-1,2-dihydrobenzene-1,2-diol dehydrogenase; tumor

Benzo(a)pyrene (BaP) is a lipophilic, widely distributed environmental toxicant that belongs to the polycyclic aromatic hydrocarbon (PAH) family of compounds. This chemical is known to cause toxicity and cancer in various organ systems. Our preliminary studies have shown that exposure of rats to BaP and other PAHs cause induction of cytochrome P450 (CYP) family of enzymes resulting in the formation and distribution of reactive metabolites in plasma and target tissues. Our studies have also shown that dietary exposure of rats to PAHs via saturated fat results in increased concentration of reactive metabolites, which stayed in target tissues for a longer time causing DNA damage compared to those that received these chemicals through unsaturated fat. Our hypothesis is that dietary fat contributes to BaP-induced colon carcinogenesis through CYP mediated epoxide and quinone pathways. The rationale behind this study is that every year 56,000 deaths are attributed to colorectal cancer in United States of America and in a great majority of the cases surveyed, consumption of well-done red meat and other saturated fats, rich in PAHs were implicated as a possible causative factor. This implies that formation and progression of colon tumors depends on altered BaP biotransformation by the type of dietary lipids ingested. We intend to test our hypothesis by studying the effects of oral exposure of adult Apc Min mice to BaP in saturated fat, using the following specific aims: 1. Investigate the potentiating effect of dietary fat on BaP-induced adenomas in small intestine and colon of adult Apc Min mice; 2. Determine the dietary fat induced alteration of BaP biotransformation enzyme activities and pharmacokinetics in Ape Min mice; 3. Assess the contribution of dietary fat to BaP-DNA adduct formation and persistence in Ape Min mice; 4. Evaluate the role of dietary fat in BaP-induced oxidative damage and isoprostane production in Apc Min mice. This pilot project is expected to provide new . information to conduct mechanism-based chemoprevention studies for colorectal carcinogenesis. In other words, information gained from these studies will help to understand the contribution of consumption of fatty foods contaminated with toxic chemicals towards the development of colorectal cancers in humans. Furthermore, the knowledge gained from these studies will help to synthesize drugs that could be used to prevent the development of tumors in colon.

苯并（a）pyrene（BAP）是属于多环子的亲脂性，广泛分布的环境有毒物 芳族碳氢化合物（PAH）化合物家族。已知这种化学物质会引起毒性和癌症 各种器官系统。我们的初步研究表明，大鼠暴露于BAP和其他PAH 导致诱导细胞色素P450（CYP）酶家族，导致形成和分布 血浆和靶组织中的反应性代谢物。我们的研究还表明，大鼠的饮食暴露 通过饱和脂肪到PAH导致反应性代谢产物的浓度增加，该代谢物留在靶标 与通过 不饱和脂肪。我们的假设是，饮食脂肪通过 CYP介导的环氧和喹酮途径。这项研究背后的理由是每年有56,000 死亡归因于美利坚合众国的大肠癌，在大多数情况下 经过调查，消耗良好的红肉和其他饱和脂肪，富含PAH被认为是 可能的病因因素。这意味着结肠肿瘤的形成和进展取决于改变 摄入的饮食脂质类型的BAP生物转化。我们打算通过研究 使用以下特定目的：1。 研究饮食脂肪对小肠和结肠BAP诱导的腺瘤的增强作用 成年APC最小小鼠； 2。确定饮食脂肪诱导的BAP生物转化酶的改变 APE Min小鼠的活动和药代动力学； 3。评估饮食脂肪对BAP-DNA加合物的贡献 猿猴小鼠的形成和持久性； 4。评估饮食脂肪在BAP诱导的氧化中的作用 APC最小小鼠的损伤和异丙烷产生。该试点项目有望提供新的。 进行基于机理的化学预防研究，以进行结直肠癌。在其他 单词，从这些研究中获得的信息将有助于了解脂肪消费的贡献 被有毒化学物质污染的食物用于人类大肠癌的发展。 此外，从这些研究中获得的知识将有助于合成可用于使用的药物 防止结肠肿瘤的发展。