STUDIES OF ALKYLATING METABOLITE BY MASS SPECTROMETRY

通过质谱法研究烷基化代谢物

• 批准号: 3898331
• 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/3898331
• 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.

与许多其他药物和外源性物质一样，呋塞米和 ipomeanol（取代的呋喃）被代谢成反应性的 与蛋白质共价结合的中间体。 的程度 结合与实验动物的肝坏死相关。 与许多产生亲电代谢物的异生物质相反， （包括结构类似物2-呋喃酰胺），无毒性剂量 观察谷胱甘肽的阈值。 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 属性的差异可能归因于 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 表征反应性物质之间形成的加合物 代谢物和谷胱甘肽，交替亲核试剂或细胞 proteins. 建议开发和应用串联质量 这些加合物的表征。 质量 光谱技术将针对两种离子进行优化 在快速原子轰击过程中产生， 母离子的活化解离。 如此发展的方法 预期具有广泛的适用性。 的说明， 反应性代谢物形成的加合物的结构 取代的呋喃将有助于更广泛地理解 亲电子药物/分子相互作用是必要的 烷基化反应的机理及意义 新药开发和药物研究过程中的事件- 诱发组织损伤。