CYTOCHROME P450 MODELS FOR RISK ASSESSMENT

用于风险评估的 CYTOCHROME P450 模型

• 批准号: 6382241
• 负责人: Jeffrey P Jones
• 金额: $ 27.16万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-02-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6382241
• 关键词: chemical addition; chemical kinetics; chemical models; cytochrome P450; electron transport; environmental toxicology; enzyme mechanism; free radical oxygen; thermodynamics

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.

描述：（改编自研究者摘要）风险评估是 各级政府将其用作成本效益分析的一部分。 自从 细胞色素 P450 酶在解毒和解毒过程中发挥着核心作用。 生物活化，细胞色素 P450 催化的预测模型将 评估环境暴露潜在风险的有用工具。 该提案概述了开发模型的步骤，这些模型可以 将实验室数据转化为 P450 的计算模型。 两个都 已经成功，但就本应用程序而言，重点是 在电子元件上。 其中电子元件占主导地位 P450 催化反应的子集，涉及小的、疏水性的 具有很少官能团或极化位点的分子。 我们有 开发了一种模型，可以准确预测 (1) 小鼠体内的 LD-50 结构多样的腈类，(2) 体外代谢率 取代的甲苯和卤代烷烃的含量，以及（3）体内的比率 吸入麻醉剂的代谢（参见 C 节）。 这个提议 概述了使我们能够扩展 P450 模型的实验 介导的反应包括更多样化的底物。 这 该提案的具体目标如下： 具体目标 1. 确定能量差异； (1)氢原子 从与不同官能团相邻的碳原子中提取， (2)一系列芳香族化合物的添加。 具体目标 2. 确定叔丁氧基 (t-ButO) 是一种良好的 P450 铁-氧物质的化学模型。 具体目标 3. 开发活性氧的计算模型 P450 的物种将使我们能够预测两种氢的速率 原子抽提和芳香加成。 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结果进行比较的实验数据库 具体目标 3 下得出的结果。可以使用实验数据 纠正计算方法中的任何缺陷。 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。 该模型将代表下一个水平 努力建立 P450 介导反应的完整模型的复杂性和 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。