Accurate prediction of drug- and chemical-induced hepatotoxicity remains to be a problem for pharmaceutical companies as well as other industries and regulators. The goal of the current study was to develop an in vitro/in silico method for the rapid and accurate prediction of drug- and chemical-induced hepatocyte injury in humans. HepaRG cells were employed for high-throughput imaging in combination with phenotypic profiling. A reference set of 69 drugs and chemicals was screened at a range of 7 concentrations, and the cellular response values were used for training a supervised classifier and for determining assay performance by using tenfold cross-validation. The results showed that the best performing phenotypic features were related to nuclear translocation of RELA (RELA proto-oncogene, NF-kB subunit; also known as NF-kappa B p65), DNA organization, and the F-actin cytoskeleton. Using a subset of 30 phenotypic features, direct hepatocyte toxicity in humans could be predicted with a test sensitivity, specificity and balanced accuracy of 73%, 92%, and 83%, respectively. The method was applied to another set of 26 drugs and chemicals with unclear annotation and their hepatocyte toxicity in humans was predicted. The results also revealed that the identified discriminative phenotypic changes were related to cell death and cellular senescence. Whereas cell death-related endpoints are widely applied in in vitro toxicology, cellular senescence-related endpoints are not, although cellular senescence can be induced by various drugs and other small molecule compounds and plays an important role in liver injury and disease. These findings show how phenotypic profiling can reveal unexpected chemical-induced mechanisms in toxicology.

药物和化学物诱导的肝毒性的准确预测对于制药公司以及其他行业和监管机构而言仍然是一个难题。当前研究的目标是开发体外/silico方法快速准确地预测药物和化学诱导的人类肝细胞损伤。HepaRG细胞与表型分析相结合用于高通量成像。在7种浓度范围内筛选了69种药物和化学物质的参考集，并将细胞反应值用于训练监督分类器并通过使用十倍交叉验证法确定测定性能。结果表明，表现最佳的表型特征与RELA（RELA原癌基因，NF-kB亚基；也称为NF-κBp65）的核易位，DNA组织和F-肌动蛋白细胞骨架有关。使用30个表型特征的子集，可以预测人类对肝细胞的直接毒性，其检测灵敏度，特异性和平衡准确度分别为73％，92％和83％，分别。将该方法应用于另一组注解不明确的26种药物和化学药品，并预测了它们对人体的肝细胞毒性。结果还表明，鉴定出的区别表型变化与细胞死亡和细胞衰老有关。尽管细胞死亡相关的终点在体外毒理学中得到了广泛应用，但细胞衰老相关的终点却没有，尽管细胞衰老可以由多种药物和其他小分子化合物诱导，并且在肝损伤和疾病中起着重要的作用。这些发现表明，表型分析可以揭示毒理学中意料之外的化学诱导机制。结果还表明，所识别的表型变化与细胞死亡和细胞衰老有关。尽管细胞死亡相关的终点在体外毒理学中得到了广泛应用，但细胞衰老相关的终点却没有，尽管细胞衰老可以由多种药物和其他小分子化合物诱导，并且在肝损伤和疾病中起着重要的作用。这些发现表明，表型分析如何揭示毒理学中意外的化学诱导机制。结果还表明，所识别的表型变化与细胞死亡和细胞衰老有关。尽管细胞死亡相关的终点在体外毒理学中得到了广泛应用，但细胞衰老相关的终点却没有，尽管细胞衰老可以由多种药物和其他小分子化合物诱导，并且在肝损伤和疾病中起着重要的作用。这些发现表明，表型分析如何揭示毒理学中意外的化学诱导机制。尽管细胞衰老可以由多种药物和其他小分子化合物诱导，并在肝损伤和疾病中起重要作用。这些发现表明，表型分析可以揭示毒理学中意料之外的化学诱导机制。尽管细胞衰老可以由多种药物和其他小分子化合物诱导，并在肝损伤和疾病中起重要作用。这些发现表明，表型分析可以揭示毒理学中意料之外的化学诱导机制。