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

项目摘要 苯并（a）芘[B（a）P]是一种亲脂性环境毒物，广泛分布于食品和空气中。这 已知化学物质会导致多种器官系统的癌症。我们的初步研究表明， 小鼠通过饱和脂肪暴露于B（a）P导致结肠息肉发病率增加，其中一些 与通过不饱和脂肪接受B（a）P的小鼠相比，小鼠暴露于B（a）P 通过饱和脂肪引起细胞色素P450家族酶的诱导，导致 与通过不饱和脂肪接受B（a）P的那些相比，活性代谢物的浓度。 类似地，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， 通过小鼠结肠中增加的F2-异前列烷（氧化应激的标志物）浓度显示。我们 中心假设是膳食脂肪通过增强B（a）P诱导的结肠癌的发生而增强B（a）P诱导的结肠癌的发生。 B（a）P的生物利用度，以及可能在组织中更大的B（a）P积累，以及更高水平的 B（a）P代谢物。一个相关的假设是，B（a）P效应是次要的生产环氧化物或 醌类，其中一些形成DNA加合物，导致遗传毒性。我们将测试我们的假设， 研究成年ApcMin小鼠口服暴露于饱和脂肪与不饱和脂肪中的B（a）P的影响， 具体目标：1。表征饱和膳食脂肪与不饱和膳食脂肪对 B（a）在ApcMin小鼠的小肠和结肠中P诱导的腺瘤和癌; 2.评估 膳食脂肪类型对B（a）P诱导的生物转化酶表达、其活性和 B（a）P代谢物在ApcMin小鼠中的分布; 3.测试B（a）P诱导的结肠癌是否 通过环氧化物-（基因组DNA加合物）或醌（醌、8-氧代-dG和乙烯基加合物）途径介导， 或者两者都有。 本项目与人类健康的相关性 在美国，每年有56，000例死亡归因于结直肠癌（CRC），并且在绝大多数病例中， 调查显示，食用全熟红肉和其他饱和脂肪，富含B（a）P， 可能的致病因素。我们的方法是新颖的，因为它使用了复制人类的小鼠模型系统 CRC情景。我们的建议的另一个新颖的方面是，它将评估B（a）P代谢途径的作用- CRC病因中的特定生物转化事件。我们的发现将作为进行 癌症的化学预防研究，并帮助合成药物，以防止或延迟结肠癌的发病。

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.