Analysis of Time-Related Metabolic Fluctuations Induced by Ethionine in the Rat
Biomolecular Medicine, Imperial College London, Sir Alexander Fleming Building, Imperial College Road, South Kensington, London, SW7 2AZ, UK. Journal of Proteome Research
(Impact Factor: 4.25).
01/2008; 6(12):4572-81. DOI: 10.1021/pr070268q
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.
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- "In metabolites profiles, 5-oxoproline was significantly increased in the liver and serum in all AFB1-treated groups. 5-Oxoproline is an intermediate in the glutathione biosynthesis pathway and has been seen to be elevated in the biofluids and tissues of rats following the administration of glutathione-depleting hepatotoxicants such as acetaminophen (Ghauri et al., 1993), bromobenzene (Waters et al., 2006) and ethionine (Skordi et al., 2007), as a potential biomarker of glutathione depletion and oxidative stress (Geenen et al., 2011). Furthermore , the expression of genes related to the detoxification response and oxidative stress (Aldh1a1, Gsta5, Abcb1b and Ces2) was also specifically upregulated in all AFB1 treatments. "
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ABSTRACT: The aim of this work was to identify mechanisms and potential biomarkers for predicting the development and progression of aflatoxin B1 (AFB1)-induced acute hepatotoxicity. In this study, microarray analysis and metabolites profiles were used to identify shifts in gene expression and metabolite levels associated with the affected physiological processes of rats treated with AFB1. Histopathological examinations and serum biochemical analysis were simultaneously performed; the results indicated that hepatotoxicity occurred in higher dosage groups. However, gene expression analysis and metabolite profiles are more sensitive than general toxicity studies for detecting AFB1-induced acute hepatotoxicity as the patterns of low-dose AFB1-treated rats in these two technique platforms were more similar to the rats in higher dosage groups than to the control rats. Integrated analysis of the results from general toxicity studies, transcriptomics and metabonomics profiles suggested that p53 signaling pathway induced by oxidative damage was the crucial step in AFB1-induced liver hepatotoxicity, whereas gluconeogenesis and lipid metabolism disorder were found to be the major metabolic effects after acute AFB1 exposure. The genes and metabolites significantly affected in common in rat liver or serum of three doses AFB1 treatments served as potential biomarkers for detecting AFB1-induced acute hepatotoxicity.
Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 02/2013; 55. DOI:10.1016/j.fct.2013.01.020 · 2.90 Impact Factor
16th Annual Symposium on Frequency Control. 1962; 02/1962
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ABSTRACT: A major charter for modern nutrition is to provide a molecular basis for health outcome resulting from different food choices and how this could be designed to maintain individual health free of disease. Nutrigenomic techniques have been developed to generate information at various levels of biological organization, i.e. genes, proteins, and metabolites. Within this frame, metabonomics targets the molecular characterization of a living system through metabolic profiling. The metabolic profiles are explored with sophisticated data mining techniques mainly based on multivariate statistics, which can recover key metabolic information to be further linked to biochemical processes and physiological events. The power of metabonomics relies on its unique ability to assess functional changes in the metabolism of complex organisms stemming from multiple influences such as lifestyle and environmental factors. In particular, metabolic profiles encapsulate information on the metabolic activity of symbiotic partners, i.e. gut microflora, in complex organisms, which represent major determinant in nutrition and health. Therefore, applications of metabonomics to nutrition sciences led to the nutrimetabonomics approach for the classification of dietary responses in populations and the possibility of optimized or personalized nutritional management.
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