TOWARD A PREDICTIVE TOXICOLOGY

走向预测毒理学

• 批准号: 2459009
• 负责人: CORWIN H HANSCH
• 金额: $ 14.41万
• 依托单位: POMONA COLLEGE
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 1998-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2459009
• 关键词: amphiphilicity; aniline; ascorbate; butylated hydroxytoluene; chemical structure function; clone cells; free radicals; glutathione; hydropathy; hydroxyl radical; phenols; prognosis; spectrometry; tocopherols; toxicology; toxicology information system

Since the advent of the Hammett equation (1935) and our extension of it (1962) to a generalized form for quantitative structure-activity relationships (QSAR), thousands of such equations have been published. Indeed, the plethora of equations in a wide variety of journals on numerous diversified systems (DNA, enzymes, organelles, cells, membranes, whole organisms) makes it impossible to keep account of what has been done. Our own databank, contains 6000 equations evenly split between physical organic chemistry and biological reactions. Each equation encapsulates a mechanistically based quantitative structure activity relationship from which predictions can be made about other congeneric molecules interacting with the same system. This is the first level of mechanistic understanding. A second level is possible when bond making or breaking occurs in the biological reaction. These QSAR can often be related to similar organic reactions via electronic terms in the QSAR. A third level of understanding comes-when the biological QSAR can be' related to each other in groups. The ultimate step is to develop relationships between groups of QSAR. We have developed a highly efficient computer program to make such comparative studies of QSAR. We are particularly interested in the toxicity of radicals. We plan systematic studies of chemicals for which we have found evidence that their toxicity depends on radical formation; i.e., aromatic compounds containing hydroxy, amino or benzylic hydrogens. We propose to do this using cell culture systems. The objective is to develop a mechanistic predictive toxicology based on physical organic chemistry tenets of QSAR.

自Hammett方程式出现以来（1935年）和我们的扩展 （1962）到定量结构活性的广义形式 关系（QSAR），已经发表了数千个此类方程式。 确实，多种期刊中的大量方程式 许多多样化的系统（DNA，酶，细胞器，细胞，膜， 整个生物）使得不可能考虑到 完毕。我们自己的数据库，包含6000个方程 物理有机化学和生物反应。 每个方程都封装了基于机械的定量结构 活动关系可以从中对其他人进行预测 同一分子与同一系统相互作用。这是第一个 机械理解水平。 当结合时可能是第二级 生物反应发生或破裂。这些Qsar经常可以 通过QSAR中的电子项与类似的有机反应有关。 当生物QSAR可能是“ 分组相互关联。最终的步骤是发展 QSAR组之间的关系。 我们已经发展了一个高度 有效的计算机程序，以进行QSAR的这种比较研究。 我们对激进分子的毒性特别感兴趣。我们计划 对化学物质的系统研究，我们发现了证据表明 它们的毒性取决于根本的形成。即，芳香化合物 含有羟基，氨基或苯基水氢。我们建议这样做 使用细胞培养系统。目的是开发机械 基于QSAR的物理有机化学原则的预测毒理学。