Background: Adverse drug reactions leading to severe defects, disease, discomfort or even death have caused various drugs to be withdrawn from the market. These effects are typically picked up during (pre-)clinical studies, but occasionally a drug slips through, because only one in more than a thousand individuals shows adverse reactions. This idiosyncrasy is potentially related to interindividual genetic variation, but such links have only been reported for a small number of drugs. The background thought for my project is that the drug and/or its metabolites make the cells more susceptible to stress and reactive oxygen species pathways that are provided by immune cells. This is essential since the immune system has a central role in mediating tissue injury after toxicant exposure. Since the liver is the major organ for drug metabolism, we are setting up a mechanism-based screen in liver cells that will serve as a tool to identify new biomarkers that can be used to identify potential adverse drug reactions. For this we use high content imaging-based RNA interference approaches to identify the signaling pathways that control the synergistic cytotoxic action of intrinsic hepatotoxicants and immune mediators.

 

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