THEORETICAL MODELS FOR CYTOCHROME P450 MEDIATED OXIDATIONS

可以预期，药物或外来化合物的抗肿瘤能力可能与药物或外来化合物的抗肿瘤能力有关。 由特定的同工酶代谢将是一个功能， 分子内不同部位发生氧化的趋势 （电子因素）和其结合特性（空间因素）。 我们开发了一个预测模型， 底物进行P450介导的氢原子提取。我们有 通过将预测的氧化速率与 一系列腈的毒性。 当仅疏水性（pi和pi）时， 2)以1/LD_（50）预测毒性，相关性较差 （r = 0.59）。 然而，当以下情况时，获得了良好的相关性（r = 0.85）： 根据疏水性和速率的组合回归毒性 常数校正代谢发生在α- 位置 在删除两种化合物后， 据认为是由P450氧化和两种具有烯烃的化合物引起的。 氧化位点，获得了对模型的微小改进（r = 0.001）。 0.90）。 与其他实验数据集的良好相关性， 文献表明，理论模型可用于预测 细胞色素P450介导的氧化的电子趋势。 B[a]P代谢的立体化学分析表明， 人类P450、五种啮齿类动物P450和细菌P450 cam都转化为 从B[a]P到最强致癌性的立体异构体。 分子动力学 被用来确定负责的特定氨基酸， 立体化学结果。 结果表明，单螺旋 一个可能在所有P450中保守的区域， 作用

It can be expected that the ability of a drug or foreign compound to be metabolized by a particular isozyme will be a function of both the tendency of various sites within the molecule to undergo oxidation (electronic factors), and its binding characteristics (steric factors). We have developed a predictive model that estimates the tendency for a substrate to undergo P450 mediated hydrogen atom abstraction. We have tested this model by correlating the predicted oxidation rates and the toxicity of a series of nitriles. When hydrophobicity alone (pi and pi 2) was used to predict toxicity (1/LD50), a poor correlation was obtained (r = 0.59). However, a good correlation (r = 0.85) was obtained when toxicity was regressed on a combination of hydrophobicity and a rate constant corrected for the fraction of metabolism occurring at the alpha- position. After deleting two compounds for which acute toxicity is not thought to result from P450 oxidation and two compounds with olefinic oxidation sites, a minor improvement on the model was obtained (r = 0.90). Good correlations with other experimental data sets available in the literature suggest that theoretical models may be used to predict the electronic tendency for cytochrome P450 mediated oxidations. Stereochemical analysis of the metabolism of B[a]P reveals that seven human P450s, five rodent P450s and the bacterial P450cam all convert B[a]P to the most potent carcinogenic stereoisomer. Molecular dynamics was used to determine the specific amino acids responsible for the stereochemical outcome. The results suggest that a single helical region, that is likely to be conserved in all P450s, plays a primary role.