Application of cytochrome P450 reactivity on the characterization of chemical compounds and its association with repeated-dose toxicity
Application of cytochrome P450 reactivity on the characterization of chemical compounds and its association with repeated-dose toxicity
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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
DOI：
10.1016/j.taap.2019.114854
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发表时间：
2020
影响因子：
3.8
通讯作者：
Kouichi Yoshinari
中科院分区：
文献类型：
--
作者：
Michiko Watanabe;Takamitsu Sasaki;Jun-ichi Takeshita;Madoka Kushida;Yuki Shimizu;Hitomi Oki;Yoko Kitsunai;Haruka Nakayama;Hitomi Saruhashi;Rui Ogura;Ryota Shizu;Takuomi Hosaka;Kouichi Yoshinari
重复剂量毒性(RDT)研究是评价化学安全性的关键研究之一。已经有一些研究试图基于化学亚结构来预测RDT终点，但建立这种方法仍然非常困难，似乎有必要对化合物进行更详细的表征。细胞色素P450(P450)具有多种形式，具有不同的底物特异性，在外源生物的解毒和代谢激活中发挥着重要作用。在这项研究中，我们研究了使用化合物的P450反应性来对化合物进行分类的可能性。共有148个具有大鼠RDT试验数据的化合物作为测试化合物，对18个人和大鼠的P450进行了抑制试验。在被测试的化合物中，82种化合物至少抑制一种P450形式。使用P450抑制谱的系统聚类分析将82个化合物分成9个组，其中一些显示出独特的化学和生物学特性。结合计算的化学描述符对P450抑制数据进行主成分分析表明，P450抑制数据的绘制方式与加载曲线中的大多数化学描述符不同。最后，P450抑制与RDT终点之间的关联分析表明，一些与肝、肾和血液学相关的终点与某些P450的抑制显著相关。我们的结果表明，P450反应性谱可以作为表征化合物的新的描述符，用于研究毒性机制和/或建立毒性预测模型。
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.