Abstract
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.
Highlights
High-Content Screening for theDrug-induced liver injury (DILI) is triggered by prescription and non-prescription drugs, as well as herbal products or dietary supplements, leading to liver impairment or damage, and in the worst case liver failure [1,2]
We review the use of in vitro high-content screening (HCS) 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
HCS multiparametric assays could be used in combination with other highly sensitive approaches, such as expression analyses [68] or toxicometabonomics [69], that could contribute as complementary assays to better predictivity and sensitivity of the human hepatotoxicity potential for new compounds
Summary
Drug-induced liver injury (DILI) is triggered by prescription and non-prescription drugs, as well as herbal products or dietary supplements, leading to liver impairment or damage, and in the worst case liver failure [1,2]. HCS assays are multiplexed cell staining tests developed to gain a better understanding of complex biological functions and mechanisms of damage to the liver or other tissues. They have become an important tool for the safety evaluation of drug candidates [11]. We review the use of in vitro HCS 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
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