Assessment of Feasibility for Developing Toxicogenomics Biomarkers by comparing in vitro and in vivo Genomic Profiles Specific to Liver Toxicity Induced by Acetaminophen

As a possible feasibility of the extrapolation between in vivo and in vitro systems, we investigated the global gene expression from both mouse liver and mouse hepatic cell line treated with hepatotoxic chemical, acetaminophen (APAP), and compared between in vivo and in vitro genomic profiles. For in vivo study, mice were orally treated with APAP and sacrificed at 6 and 24 h. For in vitro study, APAP were administered to a mouse hepatic cell line, BNL CL.2 and sampling was carried out at 6 and 24 h. Hepatotoxicity was assessed by analyzing hepatic enzymes and histopathological examination (in vivo) or lactate dehydrogenase (LDH) assay and morphological examination (in vitro). Global gene expression was assessed using microarray. In high dose APAPtreated group, there was centrilobular necrosis (in vivo) and cellular toxicity with the elevation of LDH (in vitro) at 24 h. Statistical analysis of global gene expression identified that there were similar numbers of altered genes found between in vivo and in vitro at each time points. Pathway analysis identified glutathione metabolism pathway as common pathways for hepatotoxicty caused by APAP. Our results suggest it may be feasible to develop toxicogenomics biomarkers or profiles by comparing in vivo and in vitro genomic profiles specific to this hepatotoxic chemical for application to prediction of liver toxicity.