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

Int J Mol Sci. 2020 Nov 4;21(21):8250. doi: 10.3390/ijms21218250.


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.

Keywords: and metabolomics; gene expression profiles; genome-scale metabolic models; hepatotoxicity; injury pathways; liver; mechanism.

MeSH terms

  • Acetaminophen / pharmacology
  • Acetaminophen / toxicity
  • Acute Disease
  • Amino Acids / metabolism*
  • Animals
  • Biomarkers / analysis
  • Biomarkers / metabolism
  • Bromobenzenes / pharmacology
  • Bromobenzenes / toxicity
  • Carbon Tetrachloride / pharmacology
  • Carbon Tetrachloride / toxicity
  • Chemical and Drug Induced Liver Injury / diagnosis*
  • Chemical and Drug Induced Liver Injury / genetics
  • Chemical and Drug Induced Liver Injury / metabolism
  • Chemical and Drug Induced Liver Injury / pathology
  • Gene Expression Profiling
  • Hazardous Substances / pharmacology*
  • Hazardous Substances / toxicity
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Lipid Metabolism / drug effects*
  • Lipid Metabolism / genetics
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Metabolic Networks and Pathways / drug effects
  • Metabolic Networks and Pathways / genetics
  • Metabolome / drug effects*
  • Metabolome / genetics
  • Metabolomics
  • Prognosis
  • Rats
  • Rats, Sprague-Dawley
  • Transcriptome / drug effects


  • Amino Acids
  • Biomarkers
  • Bromobenzenes
  • Hazardous Substances
  • Acetaminophen
  • Carbon Tetrachloride
  • bromobenzene