PREDICTING BIOACTIVATION OF ENVIRONMENTAL CONTAMINANTS

该提案迈出了制定通用 毒理学预测模型外源性物质的生物活化， 活性化学物质，由CYP（细胞色素P-450）识别， 作为产生各种毒性的重要途径， 化学致癌作用事实上，有人提出，大多数人 的氧化生物活化反应可以归因于氧化。 实验和理论方法将被用来描述 定量地研究了三种物质结合和催化的因素， 不同类别的化合物，可以被生物活化， 物种了解这些因素将对我们的 预测毒性的能力，并将提高我们理解 调节化学致癌作用的因素。这个模型也将粘土 在减少我们对动物模型的依赖， 人类毒性，并有助于阐明毒性机制。 在这个建议中，各种不同的能量的理论计算 催化的生物活化反应将与实验相关 数据将研究三类化合物：a）一系列腈 B）一系列氢氯氟烃，和 取代的甲苯。方法将概述用于确定 这些物质的相对结合常数和反应速率 衬底与量子化学和分子动力学技术。 初步结果表明，准确预测的比率， 反应能和结合能可以用理论模型来计算 在这个提案中描述。如果这种预测方法已经建立， 在最初开发氯氟烃替代品之前， 研究动物将被幸免，一大笔钱将 节省了开发成本。良好的相关性， 预测的代谢率和体内毒性也已被 证实了含腈化合物的代谢。新结果 表明吸入的体内人体代谢率 麻醉剂可以使用我们的AM1模型预测。我们认为这是 第一次预测人类的相对代谢率。 此外，我们已经能够确定立体化学， 特定的氨基酸残基负责激活 前致癌物苯并[a]芘到最致癌的（7R，8R]-二醇使用 P45Ocam和分子动力学。

This proposal takes the initial steps in the development of a general model for predictive toxicology. The bioactivation of xenobiotics to reactive chemical species, by the CYPs (cytochrome P-450s), is recognized as an important pathway in the generation of various toxicities and in chemical carcinogenesis. In fact, it has been proposed that the majority of oxidative bioactivation reactions can be attributed to CYP. Experimental and theoretical methods will be used to describe quantitatively the factors involved in binding and catalysis of three distinct classes of compounds that can be bioactivated to reactive species. Knowledge of these factors will have significant impact on our ability to predict toxicity and will enhance our ability to understand the factors that modulate chemical carcinogenesis. This model will also clay an important role in reducing our dependence on animal models to predict human toxicity and help in the elucidation of the mechanisms of toxicity. In this proposal theoretical calculations of the energetics of various CYP catalyzed bioactivation reactions will be correlated with experimental data. Three classes of compounds will be studied; a) a series of nitriles b) a series of hydrochlorofluorocarbons, and c) a series of para substituted toluenes. Methods will be outlined for the determination of the relative binding constants and the rates of reaction of these substrates with both quantum chemical and molecular dynamics techniques. Preliminary results show that accurate predictions of the rates of reaction and binding energies can be made with the theoretical models described in this proposal. If this predictive method had been established prior to the initial development of the HCFC replacements for CFCs many research animals would have been spared and a large sum of money would have been saved on development costs. An excellent correlation of predicted rates of metabolism with in vivo toxicity has also been confirmed for the metabolism of nitrile containing compounds. New results indicate that the in vivo human metabolic rates of the inhalation anesthetics can be predicted using our AM1 model. We believe this to be the first prediction of the relative rate of metabolism in humans. Furthermore, we have been able to determine the stereochemistry and specific amino acid residues that are responsible for activating the procarcinogen benzo[a]pyrene to the most carcinogenic (7R,8R]-diol using P45Ocam and molecular dynamics.