Gene expression analysis of precision-cut human liver slices indicate stable expression of hepatotoxicity related genes

In the process of drug development it is of high importance to test the safety of new drugs with predictive value for human toxicity. A promising approach of toxicity testing is based on changes in the gene expression profile of the liver. Toxicity screening based on animal liver cells cannot be directly extrapolated to humans due to species differences. For the prediction of human specific toxicity, we evaluated precision-cut human liver slices as in vitro model. The liver slices contain all cell types of the liver in their natural architecture. This is important since drug-induced toxicity often is a multi-cellular process, involving not only hepatocytes but also Kupffer, stellate and endothelial cells. Previously we showed that toxicogenomic analysis of rat liver slices is highly predictive for rat in vivo toxicity. In this study we investigated the levels of gene expression during incubation up to 24 hours with Affymetrix microarray technology in 10 different human livers. The analysis was mainly focused on genes related to stress and toxicity, phase-I and phase-II metabolizing enzymes and drug transporters. From the total amount of probe sets analyzed (54675) the expression of 3% changed significantly during incubation (FC>2, p<0.05). Pathway mapping showed that these differentially expressed genes were significantly associated with cytoskeleton remodeling, extracellular matrix and cell adhesion In the categories stress and toxicity, drug transporters and metabolic enzymes, changes were minimal. These results indicate that precision-cut human liver slices represent a valuable model for human in vitro hepatotoxicity testing.