Donato MaríaTeresa, Tolosa Laia
Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain.
Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain.
Antioxidants (Basel). 2021 Jan 13;10(1):106. doi: 10.3390/antiox10010106.
Drug-induced liver injury (DILI) remains a major cause of drug development failure, post-marketing warnings and restriction of use. An improved understanding of the mechanisms underlying DILI is required for better drug design and development. Enhanced reactive oxygen species (ROS) levels may cause a wide spectrum of oxidative damage, which has been described as a major mechanism implicated in DILI. Several cell-based assays have been developed as in vitro tools for early safety risk assessments. Among them, high-content screening technology has been used for the identification of modes of action, the determination of the level of injury and the discovery of predictive biomarkers for the safety assessment of compounds. In this paper, we review the value of in vitro high-content screening studies and evaluate how to assess oxidative stress induced by drugs in hepatic cells, demonstrating the detection of pre-lethal mechanisms of DILI as a powerful tool in human toxicology.
药物性肝损伤（DILI）仍然是药物研发失败、上市后警告及使用受限的主要原因。为了更好地进行药物设计和开发，需要更深入地了解DILI的潜在机制。活性氧（ROS）水平升高可能会导致广泛的氧化损伤，这被认为是DILI的主要机制。已经开发了几种基于细胞的检测方法作为早期安全风险评估的体外工具。其中，高内涵筛选技术已用于确定作用模式、损伤程度的测定以及发现用于化合物安全性评估的预测生物标志物。在本文中，我们综述了体外高内涵筛选研究的价值，并评估了如何评估药物在肝细胞中诱导的氧化应激，证明检测DILI的亚致死机制是人类毒理学中的一种强大工具。
