The time-course of metabolic events following response to a model hepatotoxin
ethionine (800 mg/kg) was investigated over
a 7 day period in rats using high-resolution (1)H NMR spectroscopic analysis of urine and multivariate statistics. Complementary information was obtained by multivariate analysis of (1)H MAS NMR spectra of intact liver and by conventional histopathology and clinical chemistry of blood plasma. (1)H MAS NMR spectra of liver showed toxin-induced
lipidosis 24 h postdose consistent with the steatosis observed by histopathology, while hypertaurinuria was suggestive of liver injury. Early biochemical changes in urine included elevation of
guanidinoacetate, suggesting impaired methylation reactions. Urinary increases in
5-oxoproline and
glycine suggested disruption of the gamma-glutamyl cycle. Signs of
ATP depletion together with impairment of the energy metabolism were given from the decreased levels in tricarboxylic acid cycle intermediates, the appearance of
ketone bodies in urine, the depletion of hepatic
glucose and
glycogen, and also
hypoglycemia. The observed increase in
nicotinuric acid in urine could be an indication of an increase in
NAD catabolism, a possible consequence of
ATP depletion. Effects on the gut microbiota were suggested by the observed urinary reductions in the microbial metabolites 3-/4-hydroxyphenyl
propionic acid,
dimethylamine, and
tryptamine. At later stages of toxicity, there was evidence of kidney damage, as indicated by the tubular damage observed by histopathology, supported by increased urinary excretion of
lactic acid,
amino acids, and
glucose. These studies have given new insights into mechanisms of
ethionine-induced toxicity and show the value of multisystem level data integration in the understanding of experimental models of toxicity or disease.