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)芘 (BaP) 是一种亲脂性、分布广泛的环境毒物，属于多环化合物 芳香烃 (PAH) 家族化合物。已知这种化学物质会导致毒性和癌症 各种器官系统。我们的初步研究表明，大鼠接触 BaP 和其他 PAHs 引起细胞色素 P450 (CYP) 酶家族的诱导，从而导致形成和分布 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 通过饱和脂肪转化为多环芳烃会导致反应性代谢物浓度增加，从而保持在目标水平 与那些接受这些化学物质的组织相比，它在组织中停留的时间更长，导致 DNA 损伤 不饱和脂肪。我们的假设是，膳食脂肪通过以下方式促进 BaP 诱导的结肠癌发生： CYP 介导的环氧化物和醌途径。这项研究背后的基本原理是，每年 56,000 在美国，绝大多数死亡病例都是结直肠癌 调查显示，食用富含多环芳烃的全熟红肉和其他饱和脂肪可能会导致 可能的致病因素。这意味着结肠肿瘤的形成和进展取决于改变 BaP 的生物转化取决于摄入的膳食脂质类型。我们打算通过研究来检验我们的假设 成年 Apc Min 小鼠口服暴露于饱和脂肪中的 BaP 的影响，采用以下具体目标： 1. 研究膳食脂肪对 BaP 诱导的小肠和结肠腺瘤的增强作用 成年 Apc Min 小鼠； 2.确定膳食脂肪诱导的BaP生物转化酶的改变 Ape Min 小鼠中的活性和药代动力学； 3. 评估膳食脂肪对 BaP-DNA 加合物的贡献 Ape Min 小鼠的形成和持久性； 4. 评估膳食脂肪在 BaP 诱导的氧化中的作用 Apc Min 小鼠的损伤和异前列腺素的产生。该试点项目预计将提供新的。 进行基于机制的结直肠癌化学预防研究的信息。在其他方面 换句话说，从这些研究中获得的信息将有助于了解脂肪消耗的贡献 被有毒化学物质污染的食物会导致人类结直肠癌的发生。 此外，从这些研究中获得的知识将有助于合成可用于 防止结肠肿瘤的发展。