Human and mouse precision-cut liver slices as translational model for idiosyncratic hepatotoxicity of clozapine

Idiosyncratic drug reactions (IDRs) are adverse drug reactions that are rare, sporadic, unpredicted by clinical trials, unrelated to drugs’ pharmacology and occur without relation to time or dose. IDRs may arise from drug interaction with inflammation that renders the liver more sensitive to injury resulting in increased toxicity.With the aim to develop a translational model to unravel the mechanism behindIDRs and to find biomarkers that can detect them, we used mouse and humanprecision-cut liver slices (PCLS) to study the influence of inflammatory reactionson the toxicity of drugs. PCLS technology is receiving increased attention as a potential ex vivo toxicological model because PCLS retain the normal tissue architecture of an intact liver with all its cell types in their natural environment. PCLS from mouse and human were incubated with clozapine (CZ) or its non-toxic analog, olanzapine (OZ), in the presence or absence of lipopolysaccharide (LPS), an inflammation inducer. Toxicity [ATP], cytokine production [CBA], transcriptomics and kinomics [microarrays] data were assessed. CZ was more toxic in mouse than human and OZ was not toxic in both. LPS aggravated the toxicity of CZ and had no influence on OZ toxicity in both mouse and human PCLS. Moreover, LPS induced an inflammatory response and increased among others TNFα, IFN-γ, IL-6 and IL-1β and their production was altered by CZ and OZ in PCLS. Both CZ and OZ decreased LPS-induced IFN-γ production but only CZ increased LPS-induced IL-1β production in both mouse and human PCLS. CZ upregulated many more genes and activated many more kinases than OZ in the presence of LPS in human PCLS. Transcriptomics data showed that complement pathways appeared to be implicated exclusively in the CZ+LPS group and not in other treatment groups in human PCLS. Based on these results, PCLS appear to be a promising ex vivo model to study mechanisms behind IDRs