THEORETICAL MODELS FOR CYTOCHROME P450 MEDIATED OXIDATIONS

细胞色素 P450 介导的氧化的理论模型

• 批准号: 3838459
• 负责人: K KORZEKWA
• 金额: --
• 依托单位: DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3838459
• 关键词: alkenes; alkyl nitrile; catalyst; chemical models; cytochrome P450; enzyme mechanism; enzyme model; free radical oxygen; hydrogen bond; hydropathy; hydroxylation; ionization; model design /development; oxidation; quantum chemistry; thermodynamics

While the oxidation of xenobiotics by cytochrome P450 usually results in detoxification, some compounds are oxidized to more toxic intermediates. An example is the metabolism of nitriles which can result in cyanide release and acute cyanide toxicity. Although previous attempts to correlate the toxicity of nitriles to their hydrophobicity have been successful within certain groups of nitriles, a diverse series of nitriles correlates poorly with hydrophobicity alone, presumably because other factors are necessary to predict the tendency for P450 mediated cyanide release. Previously, we observed a general rank-order correlation between the calculated stability of a radical and the tendency of a carbon-hydrogen bond to undergo hydrogen atom abstraction by cytochrome P450. Using the AM1 quantum chemical method, it was found that the p-nitrosophenoxy radical had the appropriate thermodynamic symmetry for hydrogen atom abstraction reactions. Using this compound as a model for the cytochrome P450 active oxygen species, a linear correlation was observed between the calculated activation enthalpy of hydrogen abstraction reactions and a combination of heat of reaction and the ionization potential of the radical formed. This relationship was used to develop a predictive model for P450 mediated nitrile toxicity which includes both hydrophobicity and tendencies for P450 oxidations. We are now in the process of expanding this model to include aromatic and olefinic oxidations. In addition, reactants and products for 54 hydroxylation and desaturation reactions were modeled and used to predict the relative tendency for each reaction to occur.

虽然细胞色素P450对外源性物质的氧化通常导致 解毒，一些化合物被氧化成毒性更大的中间体。 一个例子是腈的代谢，它可以导致氰化物 释放和急性氰化物毒性。 虽然以前的尝试， 人们已经将腈的毒性与其疏水性联系起来 在某些腈类化合物中， 仅与疏水性相关性很差，可能是因为其他 预测P450介导的氰化物的趋势是必要的 release. 以前，我们观察到一般的排名顺序之间的相关性， 自由基的计算稳定性和碳氢化合物的趋势 键进行细胞色素P450的氢原子提取。 使用 AM1量子化学方法，发现对亚硝基苯氧基 自由基对氢原子具有适当的热力学对称性 抽象反应 利用这种化合物作为细胞色素的模型 P450活性氧，观察到之间的线性相关性， 计算的氢提取反应的活化焓和 反应热和电离势的组合， 自由基形成。 这种关系被用来开发一个预测模型 对于P450介导的腈毒性，其包括疏水性和 P450氧化的趋势。 我们现在正在扩大这一模式，以包括芳香族和 烯烃氧化 此外，54的反应物和产物 羟基化和去饱和反应进行了建模，并用于预测 每个反应发生的相对趋势。