Drug-induced hepatotoxicity screening in primary mouse hepatocytes, an Omics approach.

Drug-induced hepatotoxicity is a leading cause of attrition of candidate drugs in drug development. Therefore new screening methods are necessary which predict these hazards more accurate and earlier in the drug development process. Of all in vitro hepatotoxicity models, primary human hepatocytes are considered as 'the gold standard'. However, the use of these hepatocytes is hindered by their scarcity and major inter-individual variation. These limitations may be overcome with use of primary mouse hepatocytes. Within this context changes in protein expressions in primary mouse hepatocytes, after exposure to cyclosporin A were studied using differential gel electrophoresis. Thereafter, the mRNA expression levels of these deregulated proteins from cyclosporin A-treated cells were analyzed. Cyclosporin A induced ER stress and altered the ER-Golgi transport, which may alter vesicle mediated transport and protein secretion. Moreover are the differentially expressed proteins observed upon challenge by cyclosporin A, associated with cholestatic mechanisms.

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