Reconciled rat and human metabolic networks for comparative toxicogenomics and biomarker predictions

Edik M Blais,Anders Wallqvist,Glynis L Kolling,Kristopher D Rawls,Jason A Papin,Bonnie V Dougherty,Zhuo I Li,Ping Ye

doi:10.1038/ncomms14250

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, 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.

Highlights

The laboratory rat has been used as a surrogate to study human biology for more than a century
genome-scale network reconstruction (GENRE) of Rattus norvegicus and Homo sapiens metabolism were constructed in parallel as an expansion of the Human Metabolic Reaction 2.0 database[15] (HMR2)
Compared with previous human and mouse GENREs12,13,15,31,32, iRno and iHsa captured the highest numbers of total reactions, enzymatic reactions, reactions associated with complex gene protein reaction (GPR) rules and annotations to external databases (Table 1)

Summary

Introduction

The laboratory rat has been used as a surrogate to study human biology for more than a century. 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. Understanding species-specific differences between rats and humans will be important for the interpretation of preclinical animal studies in drug development, biomarker discovery and comparative toxicogenomics analyses[2,10,11]. We construct the first comprehensive GENRE of rat metabolism and a newly updated GENRE of human metabolism We manually curate both rat and human metabolic networks in parallel to reconcile species-specific differences and facilitate cross-species comparisons. The comparative network analyses between rat and human metabolism presented here provide a novel framework for improving the translation of future preclinical studies in rats to humans

Methods

Results

Conclusion