METABOLIC ACTIVATION OF ARYLAMINES IN LEUKOCYTES

这项研究计划的目的是阐明 白细胞引起生物激活或 芳胺和相关化学品的毒性。研究将会 强调各种类型的白细胞引起 芳香胺和芳香族异羟肟酸与其共价结合 细胞大分子，这一过程可以导致 破坏正常的细胞功能，导致细胞死亡。这个 最令人感兴趣的大分子是DNA和RNA。共价 与这些核酸的结合将在 负责引起这种结合的白细胞，以及 激活细胞外的核酸也是如此。共价键 芳胺和异羟肟酸与分子间的结合 不参与新陈代谢的细胞大分子 这些化学物质的激活将预示着一种重要的 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)的潜能 和巨噬细胞)对周围细胞造成损害 已知是由于活性氧物种的释放而产生的 在这种细胞正常的“呼吸爆发”之后。这个 外源生物的存在，它们本身就容易受到 这些白细胞产物的氧化很容易改变 这些吞噬细胞造成的损害的性质。被动型 白细胞氧化芳胺和芳香胺产生的代谢产物 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令人担忧的问题。这个 强调芳胺是因为这门课的重要性。 作为药物、杀虫剂和其他物质的来源的化学物质 环境化学品。人们对异羟肟酸产生了兴趣 因为它们是已知的芳胺代谢物 主要是在肝脏中产生的，负责 部分原因是芳香胺的遗传毒性和坏死性。 羟胺酸被认为是潜伏期的形式 可转运至组织的代谢激活产物 在肝脏中产生后遍及全身。进一步 异羟肟酸的转化是其必需的 潜在的毒性将被释放。某些白细胞能够 通过机制导致异羟肟酸的最终生物活化 这一点将在本节目中进行研究。有关于 白细胞引起毒化的过程 芳胺和异羟肟酸将使科学家能够设计出 采取措施尽量减少或防止这种情况的不利影响 毒性反应对人体健康的影响。

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.