Genome-scale characterization of toxicity-induced metabolic alterations in primary hepatocytes

Context-specific Genome-scale Metabolic Network Reconstructions (GENREs) provide a means to understand cellular metabolism at a deeper level of physiological detail. Here, we use transcriptomics data from chemically exposed rat hepatocytes to constrain a GENRE of rat hepatocyte metabolism and predict biomarkers of liver toxicity using the Transcriptionally Inferred Metabolic Biomarker Response (TIMBR) algorithm. We profiled alterations in cellular hepatocyte metabolism following in vitro exposure to four toxicants (acetaminophen, carbon tetrachloride, 2,3,7,8-tetrachlorodibenzodioxin, and trichloroethylene) for six hours. TIMBR predictions were compared with paired fresh and spent media metabolomics data from the same exposure conditions. Agreement between computational model predictions and experimental data led to the identification of specific metabolites and thus metabolic pathways associated with toxicant exposure. Here, we identified changes in the TCA metabolites citrate and alph...