CHEMICAL TOXICOLOGY OF ISOCYANATES AND FORMAMIDES

异氰酸酯和甲酰胺的化学毒理学

• 批准号: 3253804
• 负责人: THOMAS A BAILLIE
• 金额: $ 15.74万
• 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 1994-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3253804
• 关键词: acetylcysteine; adduct; antineoplastics; blood proteins; chemical conjugate; chemical structure; detoxification; environmental toxicology; formamide; glutathione; glutathione reductase; hydroxylation; inhalation drug administration; isocyanates; laboratory mouse; laboratory rat; liver disorder; mass spectrometry; 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的 高活性、高毒性物质甲基异氰酸酯（MIC）毒理学 工业上用于制备氨基甲酸酯农药， 这种化合物在印度博帕尔市意外释放， 史上最严重的工业悲剧该项目还 旨在确定MIC和相关亲电氨甲酰化的作用 N-甲基甲酰胺致肝损伤的介质 (NMF)，一种实验性抗肿瘤剂，和N，N-二甲基甲酰胺（DMF）， 广泛使用的工业溶剂。有毒异氰酸酯的参与 在生物命运和三个行动的机制， 药物，即1，3-双（2-氯乙基）-l-亚硝基脲（BCNU）、卡拉塞米和 NMF，也将进行调查，重点是他们的作用， 谷胱甘肽（GSH）缀合物作为活性氨甲酰化剂。具体 该项目的目标如下： (a)为了表明，在大鼠吸入暴露于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） 胆汁和相应的巯基尿酸，S-（N-甲基氨基甲酰基） - N-乙酰半胱氨酸。（AMCC），经尿液排泄。(b)证明 SMG使血清蛋白氨基甲酰化，并确定 得到共价加合物。(c)建立一个机械基础， 合理开发MIC中毒的解毒剂，并探讨 N-乙酰半胱氨酸在这种用途中的效用。(d)阐明途径 NMF和DMF的代谢活化。(e)挑战公认的观点 DMF在α-碳原子上的代谢羟基化代表 该化合物的解毒途径。(f)调查是否 卡拉塞米在体内释放MIC，并建立 释放异氰酸酯。(g)确定体内抗肿瘤活性， SMG、AMCC和相应半胱氨酸的体外致突变性 偶联物，S-（N-甲基氨基甲酰基）半胱氨酸（SMC）。(h)为了评估 的GSH缀合物的反应性异氰酸酯，以作为活性位点定向的 谷胱甘肽还原酶的抑制剂。 一个全面的系列在体外和体内实验提出 将使用大鼠和小鼠作为动物模型。的结构解析 目的化合物的极性代谢物，以及它们的共价键 加合物的蛋白质，将基于使用国家的最先进的 分析技术，包括电喷雾电离和高 性能串联质谱。总体而言，拟议的研究 将提供有关化学毒理学的基本信息， 异氰酸酯和甲酰胺，并将有助于我们了解的 谷胱甘肽依赖过程在运输反应性有毒化学物质中的作用 in vivo.