Reconciled rat and human metabolic networks for comparative toxicogenomics and biomarker predictions
Open accessAbstract
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.
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Vitamin C and bile acid synthesis pathways are different in rats and humans.
“For instance, vitamin C and bile acid synthesis pathways are different in rats and humans (303).”
From Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease (2018) · cites this paper as [303]
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Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease
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- Authors
- Blais, E. M., Rawls, K. D., Dougherty, B. V., Li, Z. I., Kolling, G. L., Ye, P., Wallqvist, A., & Papin, J. A.
- Affiliations
- University of Virginia Health System (US)
- University of Virginia (US)
- Telemedicine & Advanced Technology Research Center (US)
- Corresponding author
- Papin, Jason A.
- ORCID
- Venue
- Nature Communications
- Published
- 2017-02-08
- Volume
- 8
- Issue
- 1
- Pages
- 14250-14250
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5309818
- OpenAlex
- W2586966203
- Cited by
- 182
- References
- 73
- Citations by year
- 2026: 14 · 2025: 23 · 2024: 19 · 2023: 15 · 2022: 25 · 2021: 31 · 2020: 18 · 2019: 17 · 2018: 12 · 2017: 7
- FWCI
- 6.14
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- U.S. Department of Defense (W81XWH, W81XWH-14-C-0054)
- National Heart, Lung, and Blood Institute (T32HL007284)
- National Institute of General Medical Sciences (T32GM008715)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Microbial Metabolic Engineering and Bioproduction
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Keywords
- genome-scale metabolic reconstruction, rat metabolism, human metabolism, Rattus norvegicus, toxicogenomics, drug-induced liver injury, metabolic biomarkers, xanthine derivatives, vitamin C biosynthesis, bile acid synthesis, drug metabolism prediction
- MeSH terms
- Animals, Humans, Models, Biological, Species Specificity, Biomarkers, Computational Biology, Gene Expression Profiling, Hepatocytes, Toxicogenetics, Rats, Metabolic Networks and Pathways, Metabolomics, Datasets as Topic
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