STUDIES OF ALKYLATING METABOLITE BY MASS SPECTROMETRY

通过质谱法研究烷基化代谢物

• 批准号: 3919065
• 负责人: SIMON J GASKELL
• 金额: --
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 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/3919065
• 关键词: alkylation; bile; biotransformation; chemical addition; chemical conjugate; covalent bond; drug metabolism; furans; furosemide; glutathione; glutathione transferase; high performance liquid chromatography; laboratory rat; liver metabolism; mass spectrometry; microsomes; peptides; toxin metabolism

In common with many other drugs and xenobiotics, furosemide and ipomeanol (substituted furans) are metabolized to reactive intermediates that covalently bind to protein. The extent of binding correlated with hepatic necrosis in experimental animals. In contrast to many xenobiotics yielding electrophilic metabolites (including the structural analogue 2-furamide), no toxic dose threshold for glutathione is observed. The proposed research seeks to elucidate the underlying principles involved in these differences between electrophilic reactive metabolites. Thus, the differences in properties may be attributable to differences in the "hardness" of electrophilicity of the metabolites or to the extent and nature of their interaction with glutathione transferases. Further understanding is dependent on the structural characterization of the adducts formed between the reactive metabolites and glutathione, alternate nucleophiles or cellular proteins. It is proposed to develop and apply tandem mass spectrometry to the characterization of these adducts. The mass spectrometric technique will be optimized with-respect to both ion production during fast atom bombardment and to collisionally activated dissociation of parent ions. The methods so developed are expected to have wide applicability. The elucidation of the structures of the adduct formed by reactive metabolites of substituted furans will contribute to a broader understanding of electrophilic drug/molecule interactions necessary for the interpretation of the mechanism and significance of alkylation events during the development of new drugs and the study of drug- induced tissue lesions.

与许多其他药物和异生物质一样，速尿和 异戊醇(取代呋喃)被代谢为反应性的 与蛋白质共价结合的中间体。其影响范围 在实验动物中，结合与肝坏死相关。 与产生亲电代谢物的许多异物相反 (包括结构类似物2-呋喃酰胺)，无毒性剂量 观察到谷胱甘肽的阈值。这项拟议的研究旨在 为了阐明这些问题所涉及的基本原则 亲电活性代谢物之间的差异。因此， 属性的不同可能归因于 代谢物亲电性的“硬度”或程度 以及它们与谷胱甘肽转移酶相互作用的性质。 进一步的理解取决于结构 反应物之间形成的加合物的表征 代谢物和谷胱甘肽，交替的亲核试剂或细胞 蛋白质。建议开发和应用串联质量 光谱对这些加合物的表征。弥撒 光谱分析技术将针对这两种离子进行优化 快原子轰击和碰撞过程中的产生 激活了母体离子的离解。这样发展出来的方法 可望具有广泛的适用性。对这一问题的解释 黄曲霉毒素活性代谢物形成的加合物的结构 取代呋喃将有助于更广泛地理解 亲电药物/分子相互作用是必要的 对烷基化反应机理和意义的解读 新药开发和药物研究中发生的事件- 诱发的组织损伤。