Metabolism and Carcinogenicity of Heterocyclic Amines

描述（由申请人提供）：结直肠癌是美国癌症死亡的主要原因之一。煮熟的红肉摄入和慢性炎症/感染都在结肠癌的病因学中发挥作用。在烹饪过程中，遗传毒性杂环胺（HCAs），即，2-氨基-3-甲基咪唑并[4，5-f]喹啉（IQ），可引发结肠癌。炎症性肠病患者的结直肠癌发病率比普通人群高20倍，发病时间早20年。在动物模型中，患者的发现是结肠粘膜持续严重炎症，被认为是导致结直肠癌发展的原因。葡聚糖硫酸钠（DSS）诱导的结肠炎是研究炎症和结肠炎相关肿瘤的动物模型。活性氮氧物质（RNOS），炎症反应的组分，有助于炎症的有害影响。RNOS催化亚硝化、氧化和硝化反应。然而，RNOS对HCA致癌性的影响尚未得到评估。这样的评估对于理解煮熟的红肉摄入量与结肠癌慢性感染/炎症之间的强烈关联至关重要。由于我们最近证明RNOS将IQ转化为N-亚硝基产物（N-NO-IQ），其形成DNA加合物并具有致突变性，因此我们假设RNOS源自炎症反应，与HCA反应形成N-亚硝基产物，从而引发结肠癌。检验这一假设的关键是鉴定和测量动物和细胞中对炎症刺激反应的N-亚硝基产物;证明N-亚硝基产物具有遗传毒性，并且在DSS处理的小鼠中HCA诱导的结肠癌增加。以下具体目标将检验我们的假设：1。研究RNOS对HCA的转化; 2.确定HCAs及其RNOS衍生的N-亚硝基产物的反应性和潜在的遗传毒性; 3.通过体外细胞系统，利用炎症模型评估N-NO-IQ及其产物的形成和代谢; 4.评估DSS诱导的结肠炎小鼠中N-NO-IQ的形成和代谢; 5.确定DSS诱导的结肠炎炎症对IQ致癌性的影响。长期目标是了解RNOS在HCA致癌中的作用。

DESCRIPTION (provided by applicant): Colorectal cancer is one of the leading causes of cancer deaths in the United States. Both cooked red meat intake and chronic inflammation/infection play a role in the etiology of colon cancer. During the cooking process, genotoxic heterocyclic amines (HCAs), i.e., 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), are formed which can initiate colon cancer. Colorectal carcinoma incidence in patients with inflammatory bowel disease is 20-fold higher and occurs 20 years earlier than the general population. Findings in patients are paralleled in animal models with persistent severe inflammation in the colonic mucosa thought to cause development of colorectal cancer. Dextran sulfate sodium (DSS)-induced colitis is an animal model for studying both inflammation and colitis-associated neoplasia. Reactive nitrogen oxygen species (RNOS), components of the inflammatory response, contribute to deleterious effects of inflammation. RNOS catalyze nitrosation, oxidation, and nitration reactions. However, the influence of RNOS on HCA carcinogenicity has not been evaluated. Such an evaluation is essential to understanding the strong association between cooked red meat intake and chronic infection/inflammation in colon cancer. Because we recently demonstrated RNOS transformation of IQ to an N-nitroso product N-NO-IQ), which forms DNA adducts and is mutagenic, we hypothesize that RNOS derived from the inflammatory response react with HCAs forming N-nitroso products that initiate colon cancer. Critical to testing this hypothesis is the identification and measurement of N-nitroso products in animals and cells responding to inflammatory stimuli; the demonstration that N-nitroso products are genotoxic and that HCA-induced colon cancer is increased in DSS-treated mice. The following specific aims will test our hypothesis: 1. Investigate HCA transformation by RNOS; 2. Determine reactivity and potential genotoxicity of HCAs and their RNOS-derived N-nitroso products; 3. Evaluate formation and metabolism of N-NO-IQ and its products by in vitro cellular systems, using inflammatory models; 4. Assess formation and metabolism of N-NO-IQ in mice with DSS-induced colitis; 5. Determine effect of DSS-induced colitis inflammation) in IQ carcinogenicity. The long-term goal is to understand the role of RNOS on HCA carcinogenesis.