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

Adverse drug reactions (ADRs) related to hepatotoxicity and drug hypersensitivity are responsible for the top two of toxicity-related drug withdrawals and there are no adequate translational strategies to predict safety. Idiosyncratic adverse drug reactions (IADRs) are ADRs that are rare and sporadic, unpredicted by clinical trials, unrelated to pharmacology of the drugs and occur without obvious relation to time or dose. IADRs may arise from drug interaction with inflammatory episodes that renders the liver more sensitive to injury resulting in increased toxicity. With the aim to develop a translational model to unravel the mechanism behind IADRs and to find biomarkers that can detect them, we used human and animal precision-cut liver slices (PCLS) to study the influence of inflammatory reactions on the toxicity of drugs. The technology of PCLS 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 paracetamol (APAP)¸ diclofenac (DF), ketoconazole (KT) or clozapine (CZ) alone or in the presence of lipopolysaccharide (LPS), an inflammation inducer. Cell viability (ATP, liver enzyme leakage) and cytokine production were assessed. Both APAP and DF were more toxic in mouse than human. LPS had no influence on APAP and DF toxicity in mouse or human when assessed by viability tests. However, APAP and DF decreased the LPS-induced IL-1β production in both species while IL-6 production was only decreased in mouse PCLS. APAP slightly increased LPS-induced TNF-α production in mouse but strongly reduced it in human PCLS, while in both species TNF-α production was increased due to DF. In contrast to APAP and DF, toxicity of KT and CZ was increased in the presence of a non-toxic dose of LPS in mouse PCLS. Interestingly, the LPS-induced IL-1β production was increased by co-incubation with both KT and CZ, a phenomenon not observed in the cases of APAP or DF. In conclusion, clear species differences were identified in the effect of the drugs on the inflammatory reactions due to LPS. Toxicity of KT and CZ is aggravated by LPS and IL-1β upregulation might be involved in here. Based on these results, PCLS appear to be a promising ex vivo model to study mechanisms behind IADRs particularly in the human liver.