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Rat precision-cut liver slices predict drug-induced cholestatic injury

Starokozhko, V., Greupink, R., van de Broek, P., Nashwa, S., Ghimire, S., de Graaf, I. & Groothuis, G., Oct-2017, In : Archives of toxicology. 91, 10, p. 3403-3413 11 p.

Research output: Contribution to journalArticleAcademicpeer-review

Drug-induced cholestasis (DIC) is one of the leading manifestations of drug-induced liver injury (DILI). As the underlying mechanisms for DIC are not fully known and specific and predictive biomarkers and pre-clinical models are lacking, the occurrence of DIC is often only reported when the drug has been approved for registration. Therefore, appropriate models that predict the cholestatic potential of drug candidates and/or provide insight into the mechanism of DIC are highly needed. We investigated the application of rat precision-cut liver slices (PCLS) to predict DIC, using several biomarkers of cholestasis: hepatocyte viability, intracellular accumulation of total as well as individual bile acids and changes in the expression of genes known to play a role in cholestasis. Rat PCLS exposed to the cholestatic drugs chlorpromazine, cyclosporine A and glibenclamide for 48 h in the presence of a 60 μM physiological bile acid (BA) mix reflected various changes associated with cholestasis, such as decrease in hepatocyte viability, accumulation and changes in the composition of BA and changes in the gene expression of Fxr, Bsep and Ntcp. The toxicity of the drugs was correlated with the accumulation of BA, and especially DCA and CDCA and their conjugates, but to a different extent for different drugs, indicating that BA toxicity is not the only cause for the toxicity of cholestatic drugs. Moreover, our study supports the use of several biomarkers to test drugs for DIC. In conclusion, our results indicate that PCLS may represent a physiological and valuable model to identify cholestatic drugs and provide insight into the mechanisms underlying DIC.
Original languageEnglish
Pages (from-to)3403-3413
Number of pages11
JournalArchives of toxicology
Volume91
Issue number10
Publication statusPublished - Oct-2017

    Keywords

  • TRANSPORTERS, INHIBITION, SALT EXPORT PUMP, FARNESOID-X-RECEPTOR, BILE-ACID, HUMAN HEPATOCYTES, INDUCED TOXICITY, CYCLOSPORINE-A, HEPARG CELLS, METABOLISM

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