Toxicant-Induced Metabolic Alterations in Lipid and Amino Acid Pathways Are Predictive of Acute Liver Toxicity in Rats

International Journal of Molecular Sciences

Irina Trenary¹  Mohsin Rahim¹  VenkatR. Pannala²  Anders Wallqvist²  Jaques Reifman²  RichardL. Printz³  JameyD. Young³  ShaneaK. Estes³  TracyP. O’Brien³  Chiyo Shiota³  Masakazu Shiota³ 

[1] Department of Chemical and Biomolecular Engineering, Vanderbilt University School of Engineering, Nashville, TN 37232, USA;Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Development Command, Fort Detrick, MD 21702, USA;Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA;

关键词: liver;    genome-scale metabolic models;    mechanism;    hepatotoxicity;    injury pathways;    gene expression profiles;   

DOI  :  10.3390/ijms21218250

来源: DOAJ

【 摘 要 】

Liver disease and disorders associated with aberrant hepatocyte metabolism can be initiated via drug and environmental toxicant exposures. In this study, we tested the hypothesis that gene and metabolic profiling can reveal commonalities in liver response to different toxicants and provide the capability to identify early signatures of acute liver toxicity. We used Sprague Dawley rats and three classical hepatotoxicants: acetaminophen (2 g/kg), bromobenzene (0.4 g/kg), and carbon tetrachloride (0.3 g/kg), to identify early perturbations in liver metabolism after a single acute exposure dose. We measured changes in liver genes and plasma metabolites at two time points (5 and 10 h) and used genome-scale metabolic models to identify commonalities in liver responses across the three toxicants. We found strong correlations for gene and metabolic profiles between the toxicants, indicative of similarities in the liver response to toxicity. We identified several injury-specific pathways in lipid and amino acid metabolism that changed similarly across the three toxicants. Our findings suggest that several plasma metabolites in lipid and amino acid metabolism are strongly associated with the progression of liver toxicity, and as such, could be targeted and clinically assessed for their potential as early predictors of acute liver toxicity.

【 授权许可】

Unknown