Precision-cut liver slices as an ex vivo model to study idiosyncratic hepatotoxicity in mouse and human

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 render the liver more sensitive to injury resulting in increased toxicity. With the aim to develop a translational model to unravel the mechanism behind IDRs and to find biomarkers that can detect them, we used mouse (M) and human (H) precision-cut liver slices (PCLS) to study the influence of inflammatory reactions on 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 M and H were incubated with paracetamol (APAP), diclofenac (DF), ketoconazole (KT) or clozapine (CZ) alone and in the presence of lipopolysaccharide (LPS), an inflammation inducer. Cell viability [ATP] and cytokine production [CBA] were assessed. APAP, DF, and CZ (but not KT) were more toxic in M than H. LPS had no influence on APAP and DF toxicity in M or H. APAP and DF slightly increased LPS-induced TNF-α production in M but strongly reduced it in H PCLS and both decreased the LPS-induced IL-1β production in both species. In contrast, toxicity of KT (only in M) and CZ (in both M and H) was aggravated in the presence of a non-toxic dose of LPS and an increase in LPS-induced IL-1β production was observed here. In conclusion, clear species differences were identified in the effect of the drugs on toxicity and on inflammatory reactions due to LPS. Toxicity of KT (only in M) and CZ (in both M and H) was aggravated by LPS, not observed in the cases of APAP or DF. A correlation appeared between increased toxicity and increased LPS-induced IL-1β production in the co-incubation of LPS and drug. Based on these results, PCLS appear to be a promising ex vivo model to study mechanisms behind IDRs