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Analysis of time-related metabolic fluctuations induced by ethionine in the rat

Skordi, E., Yap, I. K.S., Claus, S. P., Martin, F.-P. J., Cloarec, O., Lindberg, J., Schuppe-Koistinen, I., Holmes, E. and Nicholson, J. K. (2007) Analysis of time-related metabolic fluctuations induced by ethionine in the rat. Journal of Proteome Research, 6 (12). pp. 4572-4581. ISSN 1535-3893

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To link to this item DOI: 10.1021/pr070268q

Abstract/Summary

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.

Item Type:Article
Refereed:Yes
Divisions:Interdisciplinary centres and themes > Chemical Analysis Facility (CAF) > NMR (CAF)
Faculty of Life Sciences > School of Chemistry, Food and Pharmacy > Department of Food and Nutritional Sciences > Food Microbial Sciences Research Group
ID Code:25292
Publisher:American Chemical Society

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