Mica Microarray Analysis Of Hepatotoxicity In Vivo And In Vitro

In the process of drug discovery it is of great importance to develop methods to determine early markers for druginduced toxicity. The microarray technology, developed for the simultaneous analysis of a large number of genes, may be useful for the detection of toxicity in an early stage of the development of new drugs. The overall aim of the study was to identify early marker genes for different hepatotoxins. We analyzed the effect of different hepatotoxins on the gene expression profile in the rat in vivo and in vitro. As in vitro model system we used the precision-cut liver slice model, in which all cell types are present in their natural architecture. This is important since drug-induced toxicity often ia a multi-cellular process involving among others hepatocytes andKupffer cells. As model toxic compounds we used LPS (inducing inflammation), gliotoxin (apoptosis), CCL4 and paracetamol (necrosis). The results of the microarray studies show that the in vitro profiles of gene expression cluster per dose and incubation time, and when analyzed in a commercial gene expression database, can predict the toxicity and pathology observed in vivo. Each toxic compound has a specific pattern of gene expression changes. However, there were some common genes up-or downregulated with all toxic compounds. These data show that the rat liver slice system is an appropriate tool for prediction of rat liver toxicity. The same experiments and analysis are currently performed for the prediction of human specific toxicity using human liver slices.