Reconciled Rat and Human Metabolic Networks for Comparative Toxicogenomics and Biomarker Predictions
University of Virginia Charlottesville United States
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The laboratory rat has been used as a surrogate to study human biology for more than acentury. Here we present the first genome-scale network reconstruction of Rattus norvegicusmetabolism, iRno, and a significantly improved reconstruction of human metabolism, iHsa.These curated models comprehensively capture metabolic features known to distinguish ratsfrom humans including vitamin C and bile acid synthesis pathways. After reconciling network differences between iRno and iHsa, we integrate toxicogenomics data from rat and human hepatocytes, to generate biomarker predictions in response to 76 drugs. We validate comparative predictions for xanthine derivatives with new experimental data and literature based evidence delineating metabolite biomarkers unique to humans. Our results provide mechanistic insights into species-specific metabolism and facilitate the selection of biomarkers consistent with rat and human biology. These models can serve as powerful computational platforms for contextualizing experimental data and making functional predictions for clinical and basic science applications.
- Medicine and Medical Research
- Anatomy and Physiology