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Development of a co-culture model for the prediction of idiosyncratic drug-induced liver injury

: Granitzny, Anne; Hansen, Tanja; Knebel, Jan W.; Dasenbrock, Clemens; Steinberg, Pablo

Naunyn-Schmiedebergs archives of pharmacology 388 (2015), Supplement 1, S.S65, Abstract 257
ISSN: 0028-1298
ISSN: 1432-1912
Deutsche Gesellschaft für Experimentelle und Klinische Pharmakologie und Toxikologie (Annual Meeting) <81, 2015, Kiel>
Fraunhofer ITEM ()

Hepatotoxicity is one of the leading causes for withdrawals of drugs during late stages of the drug development process but also after being launched onto the market. A particularly severe and rare form of drug-induced liver injury (DILI) idiosyncratic DILI (iDILI). IDILI dependency and the underlying mechanisms is characterized by the absence of a clear dose are as yet not is the so-called fully understood. Furthermore, the prediction of iDILI from currently available pre-clinical animal studies remains difficult due to the lack of specific biomarkers. Although many drug-related mechanisms can directly induce cell death, there is growing evidence for the hypothesis that the recruitment of immune cells may play a critical role in the development of iDILI. In order to evaluate this hypothesis, which suggests that modest inflammatory stress can lower the threshold for hepatotoxicity, we established an in vitro co-culture system combining human monocytic (THP-1) with human hepatoma (HepG2) cells. With this model we aimed to identify whether the introduction of inflammatory immune cells, like monocytes, could increase the sensitivity of liver cells towards iDILI compounds. Troglitazone (TGZ), a drug that had already been withdrawn from the markets due to severe iDILI reactions, and rosiglitazone (RGZ), a compound from the same substance class, which has no potential to induce iDILI, were chosen as reference compounds. Using the WST-assay we observed a significant increase in cytotoxicity for TGZ in the co-culture model as compared to the single cell cultures while this effect was not observed with RGZ. In conclusion, for the model compounds used in this study, the co-culture model was able to differentiate between non-DILI and iDILI compounds. Our results suggest that this co-culture model could provide a useful tool for the prediction of inflammation-associated idiosyncratic drug-induced hepatotoxicity.