The time-related metabolic events in rat liver, plasma, and urine following hepatotoxic insult with
allyl formate (75 mg/kg) were studied using a combination of high-resolution liquid state and magic angle spinning (MAS) nuclear magnetic resonance (NMR) spectroscopic methods together with pattern recognition analysis. The metabonomics results were compared with the results of conventional plasma chemistry and histopathological assessments of liver damage. Various degrees of liver damage were observed in different animals, and this variation was reflected in all of the analyses. Furthermore, each analysis revealed a high degree of functional and structural recovery by the end of the study. The
allyl formate-induced changes included hepatocellular
necrosis, hepatic
lipidosis, decreased
liver glycogen and
glucose, decreased plasma
lipids, increased plasma
creatine and
tyrosine, increased urinary
taurine and
creatine, and decreased urinary TCA cycle intermediates. The observed reductions in
hepatic glycogen and
glucose suggest increased
glucose utilization and are consistent with the expected depletion of hepatic
ATP following mitochondrial impairment, assuming that there is a consequent increase in energy production from glycolysis. The increase in plasma
tyrosine is consistent with impaired
protein synthesis, a known consequence of
ATP depletion. Partial least squares-based cross-correlation of the variation in the liver and plasma NMR profiles indicated that the
allyl formate-induced increase in liver
lipids correlated with the decrease in plasma
lipids. This suggests disruption in
lipid transport from the liver to plasma, which could arise through impaired
apolipoprotein synthesis, as with
ethionine.