CHEMICAL TOXICOLOGY OF ISOCYANATES AND FORMAMIDES

异氰酸酯和甲酰胺的化学毒理学

• 批准号: 3253805
• 负责人: THOMAS A BAILLIE
• 金额: $ 15.92万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-02-05 至 1995-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3253805
• 关键词: acetylcysteine; adduct; antineoplastics; blood proteins; chemical conjugate; chemical structure; detoxification; electrospray ionization mass spectrometry; environmental toxicology; formamide; glutathione; glutathione reductase; hydroxylation; inhalation drug administration; isocyanates; laboratory mouse; laboratory rat; liver disorder; mutagen testing; nitrosourea; oxidoreductase inhibitor; poison control; solvents

The central goal of the proposed research is to study chemical aspects of the toxicology of methylisocyanate (MIC), a highly reactive and toxic agent employed industrially in the preparation of carbamate pesticides, and the compound whose accidental release in the city of Bhopal, India, brought about the worst industrial tragedy recorded in history. The project also aims to define the role of MIC and related electrophilic carbamoylating species as mediators of the hepatic damage induced by N-methylformamide (NMF), an experimental antitumor agent, and N,N-dimethylformamide (DMF), a widely-used industrial solvent. The participation of toxic isocyanates in the biological fate and mechanism of action of three antineoplastic drugs, viz. 1,3-bis(2-chloroethyl)-l-nitrosourea (BCNU), caracemide and NMF, also will be investigated, with an emphasis on the role of their glutathione (GSH) conjugates as active carbamoylating agents. The specific aims of the project are as follows: (a) To show that, following inhalation exposure of rats to MIC vapor, the glutathione conjugate S-(N-methylcarbamoyl) glutathione (SMG) is present in bile and the corresponding mercapturic acid, S-(N-methylcarbamoyl) -N-acetylcysteine. (AMCC), is excreted in urine. (b) To demonstrate that SMG carbamoylates serum proteins and to establish the nature of the resulting covalent adducts. (c) To establish a mechanistic basis for the rational development of antidotes to MIC poisoning, and to explore the utility of N-acetylcysteine for such use. (d) To elucidate the pathway(s) of metabolic activation of NMF and DMF. (e) To challenge the accepted view that metabolic hydroxylation of DMF at the alpha-carbon atom represents a route of detoxification of this compound. (f) To investigate whether caracemide liberates MIC in vivo, and to establish the origin of the released isocyanate. (g) To determine the in vivo antitumor activity, and the in vitro mutagenicity, of SMG, AMCC and the corresponding cysteine conjugate, S-(N-methylcarbamoyl) cysteine (SMC). (h) To assess the ability of GSH conjugates of reactive isocyanates to serve as active site-directed inhibitors of glutathione reductase. A comprehensive series of in vitro and in vivo experiments is proposed which will employ rats and mice as animal models. Structure elucidation of polar metabolites of the compounds of interest, and of their covalent adducts to proteins, will be based on the use of state-of-the-art analytical techniques, including electrospray ionization and high performance tandem mass spectrometry. Collectively, the proposed studies will provide fundamental information on the chemical toxicology of isocyanates and formamides, and will contribute to our understanding of the role of GSH-dependent processes in the transport reactive, toxic chemicals in vivo.

拟议研究的中心目标是研究化学方面 异氰酸甲酯 (MIC) 的毒理学，一种高反应性和毒性物质 工业上用于制备氨基甲酸酯农药，以及 该化合物在印度博帕尔市的意外泄漏导致 关于历史上最严重的工业悲剧。该项目还 旨在定义 MIC 和相关亲电氨基甲酰化的作用 N-甲基甲酰胺引起的肝损伤的介质 (NMF)，一种实验性抗肿瘤剂，和 N,N-二甲基甲酰胺 (DMF)， 一种广泛使用的工业溶剂。有毒异氰酸酯的参与 三种抗肿瘤药物的生物学命运和作用机制 毒品，即。 1,3-双(2-氯乙基)-l-亚硝基脲 (BCNU)、caracemide 和 NMF 也将受到调查，重点是它们的作用 谷胱甘肽 (GSH) 缀合物作为活性氨基甲酰化剂。具体的 该项目的目标如下： (a) 表明，大鼠吸入 MIC 蒸气后， 存在谷胱甘肽结合物 S-(N-甲基氨基甲酰基) 谷胱甘肽 (SMG) 胆汁和相应的硫醇酸，S-(N-甲基氨基甲酰基) -N-乙酰半胱氨酸。 (AMCC)，通过尿液排出。 (b) 证明 SMG 氨基甲酰化血清蛋白并确定其性质 所得共价加合物。 (c) 建立机制基础 合理开发MIC中毒解毒剂并探讨 N-乙酰半胱氨酸用于此类用途的效用。 (d) 阐明途径 NMF 和 DMF 的代谢活化。 (e) 挑战已接受的观点 DMF 在 α-碳原子处的代谢羟基化代表 该化合物的解毒途径。 (f) 调查是否 caracemide 在体内释放 MIC，并确定其起源 释放出异氰酸酯。 (g) 确定体内抗肿瘤活性，以及 SMG、AMCC 和相应半胱氨酸的体外致突变性 缀合物，S-（N-甲基氨基甲酰基）半胱氨酸（SMC）。 (h) 评估能力 反应性异氰酸酯的 GSH 缀合物作为活性位点定向 谷胱甘肽还原酶抑制剂。 提出了一系列全面的体外和体内实验 它将使用大鼠和小鼠作为动物模型。结构解析 感兴趣的化合物及其共价化合物的极性代谢物 蛋白质加合物，将基于最先进的技术的使用 分析技术，包括电喷雾电离和高 性能串联质谱。总的来说，拟议的研究 将提供化学毒理学的基本信息 异氰酸酯和甲酰胺，将有助于我们理解 谷胱甘肽依赖性过程在反应性有毒化学物质运输中的作用 体内。