公共化学
数量结构-活动关系
机制(生物学)
不良结局途径
毒性
计算生物学
药理学
化学
计算机科学
生物信息学
生物
哲学
有机化学
认识论
作者
Xuelian Jia,Xia Wen,Daniel Russo,Lauren M. Aleksunes,Hao Zhu
标识
DOI:10.1016/j.jhazmat.2022.129193
摘要
Traditional experimental approaches to evaluate hepatotoxicity are expensive and time-consuming. As an advanced framework of risk assessment, adverse outcome pathways (AOPs) describe the sequence of molecular and cellular events underlying chemical toxicities. We aimed to develop an AOP that can be used to predict hepatotoxicity by leveraging computational modeling and in vitro assays. We curated 869 compounds with known hepatotoxicity classifications as a modeling set and extracted assay data from PubChem. The antioxidant response element (ARE) assay, which quantifies transcriptional responses to oxidative stress, showed a high correlation to hepatotoxicity (PPV=0.82). Next, we developed quantitative structure-activity relationship (QSAR) models to predict ARE activation for compounds lacking testing results. Potential toxicity alerts were identified and used to construct a mechanistic hepatotoxicity model. For experimental validation, 16 compounds in the modeling set and 12 new compounds were selected and tested using an in-house ARE-luciferase assay in HepG2-C8 cells. The mechanistic model showed good hepatotoxicity predictivity (accuracy = 0.82) for these compounds. Potential false positive hepatotoxicity predictions by only using ARE results can be corrected by incorporating structural alerts and vice versa. This mechanistic model illustrates a potential toxicity pathway for hepatotoxicity, and this strategy can be expanded to develop predictive models for other complex toxicities.
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