Idiosyncratic drug-induced liver injury (DILI) is a rare adverse drug reaction resulting in liver injury, and a cause of failure in both clinical and post-approval stages of drug development. Predictive the toxicity of new chemicals entities (NCE) is a key challenge to the pharmaceutical industry (FDA, 2009). In order to avoid the use of laboratory animals, and to reduce the cost of pre clinical studies, in vitro toxicology combined the use of cellular models with the measurements of several cell health endpoints in order to predict the hepatotoxicity of NCE. Primary Human Hepatocytes and heptocyte-like cell lines such as HepaRG, Upcytes and HepG2 are commonly used in NCE safety assessment. However, standard cellular assays have shown their limitation to specifically predict DILI potential of NCE (Sison-Young et al., 2017). The era of high content analysis, and especially phenotypic screening, bring new strategy for toxicologist to predict DILIs and their underlying mechanisms, and provides an effective means to reduce drug development failures due to insufficient safety (Xu, 2015).

HCS Pharma is daily developing new cellular assay based on phenotype characterization for toxicology. See our website for more information and feel free to contact us !

Bibliography

The creation of a double strand break (DSB) is accompanied by the phosphorylation of histone H2AX. The measurement of serine 139 phosphorylated histone H2AX (γH2AX) is reported to be a marker of interest to identify potential genotoxic activity.

In order to evaluate the High Content Screening for γH2AX detection, 4 non genotoxic compounds and 9 genotoxic compounds from the ECVAM list I or II were selected to to be tested on HepG2 cell line. These cells offer the advantage to have H2AX expression data in the literature. In parallel, Human primary keratinocytes were included. Indeed these cells would be relevant for investigating skin adverse effects of topical applied xenobiotics with the advantage of High content imaging as valuable tool for screening in the early discovery phase.

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