CYTOCHROME P450 MODELS FOR RISK ASSESSMENT

描述：(改编自调查人员摘要)风险评估是 作为成本效益分析的一部分，在各级政府使用。自.以来 细胞色素P450酶在解毒和解毒中都发挥着核心作用。 生物活性，细胞色素P450催化的预测模型 评估环境暴露的潜在风险的有用工具。 这项建议概述了开发能够 将实验室数据转化为P450的计算模型。两者都有 都是成功的，但就本应用程序而言，重点是 在电子元件上。电子元件在这些产品中占主导地位 P450催化的小分子疏水反应亚群 具有很少的官能团或极化位的分子。我们有 开发了一种模型，可以准确地预测(1)小鼠的LD-50 结构多样化的一组腈，(2)体外代谢速率 取代甲苯和卤代烷，以及(3)在体内的速率 吸入麻醉剂的新陈代谢(见C节)。这项建议 概述了使我们能够扩展P450模型的实验 中介反应包括一组更多样化的底物。这个 这项建议的具体目标如下： 具体目标：1.测定氢原子的能量差 从邻近不同官能团的碳原子中提取， 和(2)加成一系列芳香族化合物。 具体目的2.建立叔丁氧基(t-Buto)是一种很好 P450铁-氧物种的化学模型。 具体目标3.建立活性氧的计算模型 P450的物种，这将使我们能够预测这两个氢的速率 原子抽提和芳香族加成。 通过完成具体目标1和2中描述的实验，我们将 建立一个可以与计算进行比较的实验数据库 在特定目标下开发的结果3.实验数据可用于 纠正计算方法中的任何不足之处。结束 产品将是一个精心构建的电子元件模型 P450介导的反应。该模型将代表下一级别的 努力建立一个完整的P450介导的反应模型的复杂性 将扩大该模型作为风险评估工具的应用范围 被P450激活的分子。

DESCRIPTION: (Adapted from the Investigator's Abstract) Risk assessment is used at every level of government as part of cost-benefit analysis. Since the cytochrome P450 enzymes play a central role in both detoxification and bioactiviation, predictive models for cytochrome P450 catalysis will be useful tools for evaluating the potential risks of environmental exposures. This proposal outlines steps towards the development of models that can translate laboratory data into computational models for the P450s. Both have been successful, but for the purposes of this application the focus is on the electronic component. The electronic component is dominant in those subsets of P450 catalyzed reactions which involve small, hydrophobic molecules that have few functional groups or polarizable sites. We have developed a model that can accurately predict (1) the LD-50 in mice of a structurally diverse set of nitriles, (2) the rates of in vitro metabolism of substituted toluenes and haloalkanes, and (3) the rates of in vivo metabolism of inhalation anesthetics (see Section C). This proposal outlines experiments that will allow us to expand our models for P450 mediated reactions to include a more diverse set of substrates. The specific aims of this proposal are as follows: Specific Aim 1. To determine the energy differences for; (1) hydrogen atom abstractions from the carbon atoms adjacent to different functional groups, and (2) addition to a series of aromatic compounds. Specific Aim 2. To establish that tert-butoxy radical (t-ButO) is a good chemical model for the iron-oxene species of P450. Specific Aim 3. To develop a computational model for the active oxygen species of P450 that will allow us to predict the rates of both hydrogen atom abstraction and aromatic addition. By completing the experiments described in Specific Aims 1 and 2, we will build a experimental database that can be compared with the computational results developed under Specific Aim 3. The experimental data can be used to correct for any deficiencies in the computational methods. The end product will be a carefully constructed model for the electronic component of P450 mediated reactions. The model will represent the next level of complexity in striving for a complete model of P450 mediated reactions and will enhance the scope of the model's utility as a risk assessment tool for molecules that are bioactivated by P450.