Species differences in the interaction between LPS and paracetamol, diclofenac and ketoconazole in precision-cut liver slices

Idiosyncratic drug reactions (IDRs) are adverse drug reactions that occur without obvious relation to time or dose and are unpredictable and sporadic. IDRs may arise due to inflammatory episodes concomitant with exposure to the drug that renders the liver more sensitive to injury resulting in increased toxicity. The aim of the study is to investigate the influence of an inflammatory reaction on the toxicity of drugs and species differences therein using human and animal precision- cut liver slices (PCLS). The technology of PCLS is receiving increased attention as a potential in vitro toxicological model because PCLS retain the normal tissue architecture of an intact liver where all cell types are present in their natural environment. Mouse and human PCLS were incubated with paracetamol (APAP), diclofenac (DF) or ketoconazole (KCZ) alone or in the presence of lipopolysaccharide (LPS) to induce an inflammatory reaction. Cell viability (ATP, liver enzyme leakage) and cytokine production were assessed. Both APAP and DF, but not KCZ, 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 increased LPS-induced TNF-α production in mouse but strongly reduced it in human PCLS, while in both species TNF-α production was increased by DF alone, but not by APAP alone. In contrast to APAP and DF, KCZ toxicity was increased in the presence of a non-toxic dose of LPS in mouse PCLS, while KCZ did not decrease the LPSinduced IL-1β production. In conclusion, KCZ toxicity is aggravated by LPS and clear species differences were identified in the effect of APAP, DF and KCZ on the inflammatory reactions induce by LPS. The role of cytokines in the effect of LPS on the toxicity of KCZ needs to be further investigated. Based on these results PCLS appear promising as an in vitro translational model to unravel the mechanism behind IDRs and to find biomarkers that can detect them