Xenobiotic metabolism can lead to metabolites with altered physicochemical and biological properties, which may differ markedly from those of their parent compounds. Thus, xenobiotic metabolism has great implication for chemical safety evaluation, which has become one of the central research areas in chemical toxicology. A plethora of analytical and in vitro methods are now available for investigating the metabolic fate of xenobiotics, especially by cytochrome P450 (CYP), at a high level of detail. However, the interpretations of metabolic reactions often face some mechanistic challenges, for example, the mechanism of the initial and rate-determining step is not easily distinguished due to the transient nature of active species of CYP, and some reactive intermediates are difficult to identify. Alternatively, computational chemistry methodologies such as quantum chemical calculations have the capacity to calculate the electronic structures for enzymatic models with hundreds of atoms, thus to be able to characterize intermediates and transition states during whole metabolic reaction course from both structural and energetics aspects, which can confront some major limitations of experimental methods. In this perspective, I first introduce state of the art experimental and computational approaches for investigating xenobiotic metabolism catalyzed by CYP, respectively. Then the strategies to harvest the synergy between experiments and computations are highlighted, which can be conducted through comparison of their analytical, kinetic, or isotope effect data at a qualitative, semiquantitative, or quantitative level to determine the metabolic mechanism. Two examples are chosen to demonstrate the synergy advantage to elucidate the metabolic mechanism of triphenyl phosphate and atrazine catalyzed by CYP, respectively, which show that the interplay between experiments and computations allows greater insight to be gained than with the isolated methods.

中文翻译：

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实验与计算之间的协同作用：揭示化学毒理学中异生物代谢机理的绿色通道。

异源生物的新陈代谢会导致其理化和生物学性质发生变化的代谢产物，其代谢产物可能与其母体化合物明显不同。因此，异源代谢对化学安全性评价具有重要意义，已成为化学毒理学研究的重点领域之一。大量的分析和体外现在可以使用多种方法来详细研究异种生物的代谢命运，尤其是通过细胞色素P450（CYP）进行研究。但是，对代谢反应的解释通常会遇到一些机械挑战，例如，由于CYP活性物种的瞬时性质，不容易区分初始和决定速率的步骤的机制，而且一些反应性中间体也难以识别。可替代地，诸如量子化学计算之类的计算化学方法具有计算具有数百个原子的酶模型的电子结构的能力，从而能够从结构和能量学方面表征整个代谢反应过程中的中间体和过渡态。面临实验方法的一些主要限制。从这个角度出发，我首先介绍了用于研究由CYP催化的异种生物代谢的最新实验和计算方法。然后重点介绍了在实验和计算之间获得协同作用的策略，可以通过在定性，半定量或定量水平上比较其分析，动力学或同位素效应数据来确定代谢机制，从而进行这些策略。选择两个实例来证明协同优势分别阐明了CYP催化的磷酸三苯酯和at去津的代谢机理，这表明与分离方法相比，实验和计算之间的相互作用能获得更大的洞察力。我首先介绍用于研究由CYP催化的异源生物代谢的最新实验和计算方法。然后重点介绍了在实验和计算之间获得协同作用的策略，可以通过在定性，半定量或定量水平上比较其分析，动力学或同位素效应数据来确定代谢机制，从而进行这些策略。选择两个实例来证明协同优势分别阐明了CYP催化的磷酸三苯酯和at去津的代谢机理，这表明与分离方法相比，实验和计算之间的相互作用能获得更大的洞察力。我首先介绍用于研究由CYP催化的异源生物代谢的最新实验和计算方法。然后重点介绍了在实验和计算之间获得协同作用的策略，可以通过在定性，半定量或定量水平上比较其分析，动力学或同位素效应数据来确定代谢机制，从而进行这些策略。选择两个实例来证明协同优势分别阐明了CYP催化的磷酸三苯酯和at去津的代谢机理，这表明与分离方法相比，实验和计算之间的相互作用能获得更大的洞察力。然后重点介绍了在实验和计算之间获得协同作用的策略，可以通过在定性，半定量或定量水平上比较其分析，动力学或同位素效应数据来确定代谢机制，从而进行这些策略。选择两个实例来证明协同优势分别阐明了CYP催化的磷酸三苯酯和at去津的代谢机理，这表明与分离方法相比，实验和计算之间的相互作用能获得更大的洞察力。然后重点介绍了在实验和计算之间获得协同作用的策略，可以通过在定性，半定量或定量水平上比较其分析，动力学或同位素效应数据来确定代谢机制，从而进行这些策略。选择两个实例来证明协同优势分别阐明了CYP催化的磷酸三苯酯和at去津的代谢机理，这表明与分离方法相比，实验和计算之间的相互作用能获得更大的洞察力。