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

苯并(A)芘(BaP)是一种亲脂性强、分布广泛的环境毒物，属于多环化合物。 芳香烃(PAH)类化合物。这种化学物质已知会在人体内引起毒性和癌症。 各种器官系统。我们的初步研究表明，大鼠暴露在苯并(A)苯和其他多环芳烃中 诱因诱导细胞色素P450(CYP)家族酶的形成和分布 血浆和靶组织中的反应性代谢物。我们的研究还表明，老鼠的饮食暴露 通过饱和脂肪进入多环芳烃会导致反应性代谢物浓度增加，并停留在目标位置。 导致DNA损伤的组织比通过 不饱和脂肪。我们的假设是，膳食脂肪通过以下途径促进BaP诱导的结肠癌的发生 CYP介导的环氧化物和苯二酚途径。这项研究背后的理论基础是，每年有56,000 在美利坚合众国和绝大多数病例中，死亡归因于结直肠癌。 调查显示，食用熟透的红肉和其他富含多环芳烃的饱和脂肪被认为是 可能的致病因素。这意味着结肠肿瘤的形成和发展依赖于改变 BaP的生物转化由摄入的膳食脂肪的类型决定。我们打算通过研究 成年APC-Min小鼠口服饱和脂肪中苯并(A)苯的影响，目的如下：1. 探讨膳食脂肪对BaP诱发的小鼠小肠和结肠腺瘤的增强作用 成年APC Min小鼠；2.测定膳食脂肪对BaP生物转化酶的影响 APE-Min小鼠体内活性及药代动力学研究3.评价膳食脂肪对BaP-DNA加合物的贡献 APE-MIN小鼠的形成和持久性；4.评价膳食脂肪在BaP诱导的氧化中的作用 APC小鼠的损伤和异前列腺素的产生。这一试点项目预计将提供新的。 对结直肠癌发生进行基于机制的化学预防研究的信息。在其他 从这些研究中获得的信息将有助于理解脂肪消费的贡献 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。

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.