MECHANISM OF TETRANITROMETHANE TOXICITY AND CARCINOGENICITY

四硝基甲烷毒性和致癌机制

• 批准号: 3855856
• 负责人: D L MORGAN
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3855856
• 关键词: DNA; chemical carcinogenesis; cytotoxicity; high performance liquid chromatography; lung; lung alveolus; nitroalkane; nucleotide metabolism; protein metabolism; respiratory pharmacology; respiratory toxin; toxin metabolism

The objective of this project is to investigate the mechanism(s) of tetranitromethane (TNM) pulmonary toxicity and carcinogenicity. This project will include studies of the reactions of TNM with cellular DNA and proteins, pharmacokinetics and metabolism, comparison of nasal and alveolar carcinogenicity, and comparison with related nitro-substituted hydrocarbons. Initial experiments were designed to evaluate the in vitro reaction of TNM with purified nucleosides. TNM was added to 10 milli-M solutions of adenosine, guanosine, thymidine, and cytosine in phosphate buffer (pH 7.0, 37 C) for up to 24 hours. Samples were removed and analyzed by high pressure liquid chromatography (HPLC) for the presence of TNM-nucleosides under these reaction conditions. The only products detected by HPLC were the unmodified nucleosides, TNM and nitroform (a degradation product of TNM). Experiments are planned to investigate whether TNM reacts with purified DNA in vitro. The DNA will be reacted with TNM and analyzed by HPLC for modified nucleotides. Subsequent experiments will evaluate the potential reaction of TNM with proteins. associated with DNA and possibly evaluate DNA strand breaks in cells treated with TNM in vitro.

该项目的目的是研究 四硝基甲烷 (TNM) 肺毒性和致癌性。 这 项目将包括 TNM 与细胞 DNA 反应的研究 蛋白质、药代动力学和代谢、鼻腔和肺泡的比较 致癌性以及与相关硝基取代物的比较 碳氢化合物。 最初的实验旨在评估体外 TNM 与纯化核苷的反应。 TNM 添加至 10 milli-M 腺苷、鸟苷、胸苷和胞嘧啶的磷酸盐溶液 缓冲液（pH 7.0，37°C）最多 24 小时。 样品被取出并 通过高压液相色谱 (HPLC) 分析是否存在 这些反应条件下的 TNM-核苷。 唯一的产品 HPLC 检测到未修饰的核苷、TNM 和硝基仿（a TNM 的降解产物）。 计划进行实验来研究 TNM 是否在体外与纯化的 DNA 发生反应。 DNA将会发生反应 使用 TNM 并通过 HPLC 分析修饰的核苷酸。 随后的 实验将评估 TNM 与蛋白质的潜在反应。 与 DNA 相关并可能评估细胞中的 DNA 链断裂 体外TNM治疗。