CYTOCHROME P450 MODELS FOR RISK ASSESSMENT

描述：（改编自研究者摘要）风险评估是 作为成本效益分析的一部分在各级政府使用。 以来 细胞色素P450酶在解毒和 生物活性，细胞色素P450催化的预测模型将是 评估环境暴露潜在风险的有用工具。 该提案概述了为开发模型而采取的步骤，这些模型可以 将实验室数据转化为P450的计算模型。 两 已经取得了成功，但对于本申请的目的，重点是 在电子元件上。 电子元件在那些 P450催化的反应的子集，其涉及小的、疏水的 具有很少官能团或可极化位点的分子。 我们有 开发了一个模型，可以准确地预测（1）LD-50的小鼠， 结构多样的腈，（2）体外代谢率 取代的甲苯和卤代烷，和（3）在体内的速率 吸入麻醉剂的代谢（见C节）。 这项建议 概述了实验，这将使我们能够扩大我们的模型为P450 介导的反应，以包括更多样化的一组底物。 的 这项建议的具体目标如下： 具体目标1。 为了确定能量差：（1）氢原子 从与不同官能团相邻的碳原子中提取， 和（2）加成到一系列芳族化合物中。 具体目标2。 为了确定叔丁氧基自由基（t-ButO）是一个好的 P450的铁氧物种的化学模型。 具体目标3。 为了建立一个计算模型， P450的种类，这将使我们能够预测氢和 原子抽象和芳香族加成。 通过完成具体目标1和2中描述的实验，我们将 建立一个实验数据库，可以与计算数据库进行比较。 根据具体目标3制定的成果。 实验数据可用于 以纠正计算方法中的任何缺陷。 年底 产品将是一个精心构造的电子元件模型， P450介导的反应。 该模型将代表下一个级别的 复杂性在争取一个完整的模型P450介导的反应， 将扩大该模型作为风险评估工具的实用范围， 被P450生物激活的分子。

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.