DNA DAMAGE INDUCED BY PANCREATROPIC NITROSAMINES

胰亚硝胺引起的 DNA 损伤

• 批准号: 3184801
• 负责人: DEMETRIUS Michael KOKKINAKIS
• 金额: $ 19.85万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-08-01 至 1991-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3184801
• 关键词: DNA repair; carcinogen testing; chemical addition; chemical carcinogen; chemical carcinogenesis; chemical structure function; dietary aminoacid; dietary proteins; kidney neoplasms; liver neoplasms; lung neoplasms; molecular oncology; nitrosamines; nitroso compounds; nutrition related tag; pancreas neoplasms; radiotracer; toxin metabolism

N-Nitroso-2, 6-dimethylmorpholine (NNDM), N-Nitrosobis(2- oxopropyl)amine (BOP), N-Nitrosobis(2-hydroxypropyl)amine (BHP), and N-Nitroso(2-hydroxypropyl) (2-oxopropyl) amine (HPOP) induce tumors of the pancreas, lungs, gallbladder, kidneys and bladder in hamsters and upper respiratory tract, esophagus, liver, and kidney tumors in rats. Organotropy of these carcinogens depends on dose, sex, frequency and route of administration. Differences between species in pancreas carcinogenesis and between sexes in liver carcinogenesis are marked and useful in the elucidation of the mechanism of action of these carcinogens. It is proposed to study the relationships among metabolism, tissue injury and carcinogenesis in rats and hamsters treated mainly with HPOP, but also with NNDM and BHP. The aims of this study are: 1) Develop the methodology to characterize and quantitate DNA adducts which are formed and persist in various tissues of hamsters and rats during continuous administration of NNDM, BHP and HPOP. 2) Design regimens of continuous administration of these carcinogens which will cause a high incidence of pancreatic tumors. 3) Measure labeling of tissue and DNA of target and nontarget organs during treatment of hamsters and rats with radiolabeled nitrosamines, and also evaluate possible relations between tumor induction and persistence of various DNA adducts. 4) Evaluate the rate of repair of various adducts by measuring the decline of their concentration in DNA and tissues of animals treated either with a single dose of carcinogen or continuously for 7 days. 5) Test the capacity of rats and hamsters to metabolize xenobiotics including the carcinogenic nitrosamines following the treatment period. Also test the activity of phase I and phase II enzymes in the liver and the ability of various tissues to repair 06 MeGuanosine following the treatment with carcinogenic nitrosamines. 6) Investigate the levels of adducts and the rate of their repair in component cells of the pancreas and liver of animals undergoing treatment with HPOP or following such treatment. 7) Examine the effect of low protein diet, methionine-deficient diet and inhibitors of sulfation of HPOP on the carcinogenicity of HPOP in hamsters. Evaluate the effect of such treatment on the formation and repair of DNA adducts in various organs of the animals.

N-亚硝基-2，6-二甲基吗啉（NNDM）、N-亚硝基双（2- 氧代丙基）胺（BOP）、N-亚硝基双（2-羟丙基）胺 (BHP)和N-亚硝基（2-羟丙基）（2-氧代丙基）胺 （HPOP）诱发胰腺、肺、胆囊、肾脏的肿瘤 仓鼠的膀胱和上呼吸道，食道， 肝脏和肾脏肿瘤。 这些的有机性 致癌物质取决于剂量，性别，频率和途径， 局 胰腺的种属差异 肝癌发生的性别差异 在阐明作用机制中显著且有用 这些致癌物质。 建议研究这些关系 在大鼠的代谢、组织损伤和致癌作用中， 主要用HPOP处理的仓鼠，但也用NNDM和 BHP。 本研究的目的是：1）发展方法学， 表征和定量形成的DNA加合物， 持续存在于仓鼠和大鼠的各种组织中， NNDM、BHP和HPOP的管理。 2)设计方案 这些致癌物质的持续使用会导致 胰腺肿瘤发病率高。 3)测量组织标记 治疗期间靶器官和非靶器官的DNA 仓鼠和大鼠与放射性标记的亚硝胺， 评估肿瘤诱导与 各种DNA加合物的持久性。 4)评估的比率 修复各种加合物通过测量其下降 在DNA和动物组织中的浓度， 单剂量致癌物或连续7天。 5)测试 大鼠和仓鼠代谢外源性物质的能力，包括 致癌的亚硝胺治疗期后。 同时检测肝脏I相和II相酶的活性 以及各种组织修复06 MeGuanosine的能力 致癌物质亚硝胺治疗后死亡 六、 研究加合物的水平及其修复率， 动物胰腺和肝脏的组成细胞 使用HPOP治疗或在此类治疗后治疗。 7)审查 低蛋白饮食、蛋氨酸缺乏饮食和 HPOP硫酸化抑制剂对HPOP致癌性的影响 仓鼠 评估这种治疗对 DNA加合物的形成和修复在各种器官的 动物