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中起作用。在蒸煮过程中，形成遗传毒性杂环胺（HCAs），即2-氨基-3-甲基咪唑[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是一般人群的20倍，发生时间比一般人群早20年。在被认为导致结直肠癌发展的结肠黏膜持续严重炎症的动物模型中，患者的发现与此相似。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（RNOS）是炎症反应的组成部分，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价。这样的评估对于理解熟红肉摄入与结肠癌慢性感染/炎症之间的强烈联系至关重要。由于我们最近证明RNOS将IQ转化为n -亚硝基产物（N-NO-IQ），形成DNA加合物并具有诱变性，我们假设来自炎症反应的RNOS与HCAs反应形成n -亚硝基产物，引发结肠癌。验证这一假设的关键是识别和测量动物和细胞对炎症刺激的反应中的n -亚硝基产物；证明n -亚硝基产物具有遗传毒性，并且hca诱导的结肠癌在dss治疗小鼠中增加。以下具体目标将检验我们的假设：观察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遗传毒性；3. 利用炎症模型评估体外细胞系统N-NO-IQ及其产物的形成和代谢；4. 评价dss诱导结肠炎小鼠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癌变中的作用。

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.