METABOLIC ACTIVATION OF ARYLAMINES IN LEUKOCYTES

白细胞中芳胺的代谢激活

• 批准号: 3251125
• 负责人: MICHAEL D CORBETT
• 金额: $ 10.42万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-06-01 至 1992-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3251125
• 关键词: DNA; N acylation; RNA; acylation; aniline; binding proteins; biphenylamines; bone marrow; cell type; centrifugation; chemical binding; chemical reaction; chemical structure function; chemical synthesis; covalent bond; cyclic amine; enzyme mechanism; high performance liquid chromatography; human tissue; hydroxamate; laboratory rat; leukocytes; macrophage; monocyte; neutrophil; nitrosamines; phenylamide; scintillation counter; sedimentation; tissue /cell culture; toxicant interaction; toxin metabolism

The objective of this research program is to elucidate the processes by which leukocytes cause the bioactivation or toxification of arylamines and related chemicals. Research will emphasize the ability of the various types of leukocytes to cause arylamines and aromatic hydroxamic acids to bind covalently with cellular macromolecules, a process which can lead to the disruption of normal cell function and cause cell death. The macromolecules of greatest interest are DNA and RNA. Covalent binding to these nucleic acids will be studied both within the leukocytes which are responsible for causing such binding, and also to nucleic acids outside the activating cells. The covalent binding of arylamines and hydroxamic acids to the macromolecules of cells that are not involved in the metabolic activation of such chemicals would indicate an important mechanism by which leukocytes can damage neighboring cells. The potential for phagocytic leukocytes (granulocytes, monocytes and macrophages) to cause damage to surrounding cells is already known to result from the release of reactive oxygen species following the normal "respiratory burst" of such cells. The presence of xenobiotics, which are themselves susceptible to oxidation by these leukocyte products, could readily alter the nature of damage caused by these phagocytic cells. The reactive metabolites produced by leukocyte oxidation of arylamines and hydroxamic acids are known to bind to nucleic acids; therefore, the potential for genotoxic effects is of major concern. The emphasis on arylamines is because of the importance of this class of chemicals as a source for pharmaceuticals, pesticides and other environmental chemicals. The interest in hydroxamic acids arises from the fact that they are known to be arylamine metabolites that are produced primarily in the liver, and which are responsible in part for the genotoxic and necrotic properties of arylamines. Hydroxiamic acids are thought to be latentiated forms of metabolic activation products that can be transported to tissues throughout the body after being produced in the liver. Further transformation of hydroxamic acids is necessary for their potential toxicity to be released. Certain leukocytes are able to cause the final bioactivation of hydroxamic acids by mechanisms that will be studied in this program. A knowledge of the processes by which leukocytes cause the toxification of arylamines and hydroxamic acids will enable scientists to devise measures to minimize or prevent the adverse effects of such toxification reactions on human health.

这项研究计划的目的是阐明 白细胞引起生物活化的过程，或 芳胺及相关化学品的精制。 研究将 强调各种类型的白细胞的能力， 芳胺和芳族异羟肟酸共价结合 细胞大分子，这一过程可以导致 破坏正常细胞功能并导致细胞死亡。 的 最感兴趣的大分子是DNA和RNA。 共价 结合这些核酸将研究内， 负责引起这种结合的白细胞，和 也与激活细胞外的核酸有关。 共价 芳胺和异羟肟酸与 不参与代谢的细胞大分子 这些化学物质的激活将表明一个重要的 白细胞可以破坏邻近细胞的机制。 吞噬白细胞（粒细胞、单核细胞）的潜力 和巨噬细胞）对周围细胞造成损害已经是 已知是由活性氧物质的释放引起的 在这些细胞的正常“呼吸爆发”之后。 的 外源性物质的存在，它们本身容易受到 这些白细胞产物的氧化，可以很容易地改变 这些吞噬细胞造成的损害的性质。 反应性 由白细胞氧化芳胺产生的代谢物， 已知异羟肟酸与核酸结合;因此， 潜在的遗传毒性效应是主要关切。 的 强调芳胺是因为这类化合物的重要性 作为药品、农药和其他化学品来源的化学品 环境化学品。 对异羟肟酸的兴趣 因为已知它们是芳胺代谢物 主要由肝脏产生， 部分原因是芳胺的遗传毒性和坏死特性。 羟肟酸被认为是潜在形式的 可转运至组织的代谢活化产物 在肝脏中产生后遍布全身。 进一步 异羟肟酸的转化是必要的， 释放潜在的毒性。 某些白细胞能够 导致异羟肟酸的最终生物活化， 这将在这个项目中进行研究。 的知识 白细胞引起白细胞变性的过程 芳基胺和异羟肟酸将使科学家能够设计出 采取措施，以尽量减少或防止这种 对人体健康的过敏反应。