TOWARD A PREDICTIVE TOXICOLOGY

走向预测毒理学

• 批准号: 2157036
• 负责人: CORWIN H HANSCH
• 金额: $ 14.69万
• 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/2157036
• 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.

自从哈米特方程（1935）的出现及其扩展以来 （1962）定量结构活动的广义形式 关系（QSAR），已经发布了数千个这样的方程。 事实上，各种期刊中都有大量的方程 许多多样化的系统（DNA、酶、细胞器、细胞、膜、 整个有机体）使得不可能记录已经发生的事情 完毕。我们自己的数据库包含 6000 个方程，均匀分布在 物理有机化学和生物反应。 每个方程都封装了一个基于机械的定量结构 活动关系，从中可以对其他活动做出预测 与同一系统相互作用的同类分子。这是第一个 机械理解水平。 当粘合时，第二个级别是可能的 制造或破坏发生在生物反应中。这些 QSAR 通常可以 通过 QSAR 中的电子术语与类似的有机反应相关。 第三个层次的理解来了——生物QSAR何时可以“ 群体中彼此相关。最终的一步是开发 QSAR 组之间的关系。 我们开发了高度 有效的计算机程序对 QSAR 进行此类比较研究。 我们对自由基的毒性特别感兴趣。我们计划 对化学品的系统研究，我们发现证据表明 它们的毒性取决于自由基的形成；即芳香族化合物 含有羟基、氨基或苄基氢。我们建议这样做 使用细胞培养系统。目标是开发一种机制 基于 QSAR 物理有机化学原理的预测毒理学。