Reconciled rat and human metabolic networks for comparative toxicogenomics and biomarker predictions.
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, and a significantly improved reconstruction of human metabolism, iHsa. These curated models comprehensively capture metabolic features known to distinguish rats from 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.
Department of Biomedical Engineering, University of Virginia, Box 800759, Health System, Charlottesville, Virginia 22908, USA.
Edik M
EM
Blais
Department of Biomedical Engineering, University of Virginia, Box 800759, Health System, Charlottesville, Virginia 22908, USA.
Kristopher D
KD
Rawls
Department of Biomedical Engineering, University of Virginia, Box 800759, Health System, Charlottesville, Virginia 22908, USA.
Bonnie V
BV
Dougherty
Department of Biomedical Engineering, University of Virginia, Box 800759, Health System, Charlottesville, Virginia 22908, USA.
Zhuo I
ZI
Li
Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA.
Glynis L
GL
Kolling
Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, US Army Medical Research and Materiel Command, Fort Detrick, Maryland 21702, USA.
Ping
P
Ye
Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, US Army Medical Research and Materiel Command, Fort Detrick, Maryland 21702, USA.
Anders
A
Wallqvist
Department of Biomedical Engineering, University of Virginia, Box 800759, Health System, Charlottesville, Virginia 22908, USA.
Jason A
JA
Papin
D000818:Animals; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D019295:Computational Biology / Q000379:methods*; D066264:Datasets as Topic; D020869:Gene Expression Profiling; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D055432:Metabolomics / Q000379:methods; D008954:Models, Biological; D051381:Rats; D013045:Species Specificity; D043922:Toxicogenetics / Q000379:methods*
D015415:Biomarkers