Toxicogenomics of precision-cut liver slices for prediction of human liver toxicity

Abstract

Hepatotoxicity is one of the major causes of adverse drug reactions and withdrawal of drugs from the market. Prediction of hepatotoxicity based on animal models is often not successful due to species differences between animals and humans. Therefore there is a need to screen new drugs for hepatotoxicity in human at an earlier stage. The aim of this study was to validate human precision-cut liver slices (PCLS) as an ex vivo model to predict drug-induced hepatotoxicity and unravel the possible mechanisms involved in human. These PCLS represent a mini “liver-model” that closely resembles the human liver from which it is prepared, with all cell types present in their original tissue matrix configuration. Human PCLS were exposed to hepatotoxicants known to cause liver necrosis, liver cholestasis or idiosyncratic toxicity. Gene expression analysis was performed and identified the genes (among the total of 20,000 genes) that were regulated by the hepatotoxic drugs. Moreover, the role of those regulated genes in signalling pathways, which can play a role in the toxicity, was revealed. We were able to identify gene patterns that could discriminate the different groups of hepatotoxicants. Our results indicate that in the future this human PCLS model can be used to identify and characterize adverse reactions of drugs or chemicals in man. The use of human tissue in addition to animal experiments will contribute to a better prediction of toxicity in humans and also to reduction in the use of experimental animals for toxicology research and drug development