Repeated-dose toxicity (RDT) studies are one of the critical studies to assess chemical safety. There have been some studies attempting to predict RDT endpoints based on chemical substructures, but it remains very difficult to establish such a method, and a more detailed characterization of chemical compounds seems necessary. Cytochrome P450s (P450s) comprise multiple forms with different substrate specificities and play important roles in both the detoxification and metabolic activation of xenobiotics. In this study, we investigated possible use of P450 reactivity of chemical compounds to classify the compounds. A total of 148 compounds with available rat RDT test data were used as test compounds and subjected to inhibition assays against 18 human and rat P450s. Among the tested compounds, 82 compounds inhibited at least one P450 form. Hierarchical clustering analyses using the P450 inhibitory profiles divided the 82 compounds into nine groups, some of which showed characteristic chemical and biological properties. Principal component analyses of the P450 inhibition data in combination with the calculated chemical descriptors demonstrated that P450 inhibition data were plotted differently than most chemical descriptors in the loading plots. Finally, association analyses between P450 inhibition and RDT endpoints showed that some endpoints related to the liver, kidney and hematology were significantly associated with the inhibition of some P450s. Our present results suggest that the P450 reactivity profiles can be used as novel descriptors for characterizing chemical compounds for the investigation of the toxicity mechanism and/or the establishment of a toxicity prediction model.

中文翻译：

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细胞色素P450反应性在化合物表征中的应用及其与重复剂量毒性的关系。

重复剂量毒性（RDT）研究是评估化学安全性的关键研究之一。已经进行了一些研究，试图基于化学亚结构预测RDT终点，但是建立这种方法仍然非常困难，对化学化合物进行更详细的表征似乎是必要的。细胞色素P450（P450）包含具有不同底物特异性的多种形式，并且在异生物素的解毒和代谢活化中均起着重要作用。在这项研究中，我们研究了化合物的P450反应性对化合物进行分类的可能用途。总共148种具有可用大鼠RDT测试数据的化合物被用作测试化合物，并对18种人类和大鼠P450进行了抑制分析。在测试的化合物中，有82种化合物抑制了至少一种P450形式。使用P450抑制谱进行的层次聚类分析将82种化合物分为9组，其中一些具有特定的化学和生物学特性。对P450抑制数据的主成分分析与计算得出的化学描述符相结合，表明P450抑制数据的绘制与加载图中大多数化学描述符的绘制方式不同。最后，P450抑制作用与RDT终点之间的关联分析表明，与肝脏，肾脏和血液学有关的某些终点与某些P450的抑制作用显着相关。我们目前的结果表明，P450反应性谱可以用作表征化学物质以研究毒性机理和/或建立毒性预测模型的新型描述符。