Reconciled Rat and Human Metabolic Reconstructions for Comparative Toxicogenomics Analyses

Abstract

The laboratory rat has been used as a surrogate to study human biology for more than a century. Here, we present the first genome-scale network reconstruction of Rattus norvegicus metabolism (iRno) reconciled with a substantially curated and updated human metabolic network reconstruction (iHsa). Inclusion of 33 rat-specific, 37 human-specific, and 8220 shared reactions enabled the models to successfully predict known metabolic functions unique to rats including vitamin C and rodent-specific bile acid synthesis. To investigate systems-level differences between rats and humans, we simulated the toxicological effects of 70 compounds on rat and human hepatocytes using gene expression data from the Japanese Toxicogenomics Project. Comparative analyses revealed that toxicant-induced changes were consistent within fatty acid and amino acid metabolism and inconsistent within bile acid and glutathione metabolism. These models will serve as powerful computational platforms for contextualizing experimental data and making functional predictions consistent with rat and human biology for clinical and basic science applications. Importantly, resolving the known differences between rats and humans has contributed to the most comprehensive and curated human model available to date.