title: An integrated metabonomic investigation of acetaminophen toxicity in the mouse using NMR spectroscopy.
abstract: An integrated metabonomics study using high-resolution 1H NMR spectroscopy has been applied to investigate the biochemical composition of intact liver tissue (using magic angle spinning), liver tissue extracts, and blood plasma samples obtained from control and acetaminophen-treated mice. Principal components analysis was used to visualize similarities and differences in biochemical profiles. The time- and dose-dependent biochemical effects of acetaminophen were related to the drug toxicity, as determined using histopathology. Metabolic effects in intact liver tissue and lipid soluble liver tissue extracts from animals treated with the high dose level of acetaminophen included an increase in lipid triglycerides and monounsaturated fatty acids together with a decrease in polyunsaturated fatty acids, indicating mitochondrial malfunction with concomitant compensatory increase of peroxisomal activity. In addition, a depletion of phospholipids was observed in treated liver tissue, which suggested an inhibition of enzymes involved in phospholipid synthesis. There was also a depletion in the levels of liver glucose and glycogen. In addition, the aqueous soluble liver tissue extracts from high dose animals also revealed an increase in lactate, alanine, and other amino acids, together with a decrease in glucose. Plasma spectra showed increases in glucose, acetate, pyruvate, and lactate. These observations all provide evidence for an increased rate of glycolysis. These findings could indicate a mitochondrial inability to use pyruvate in the citric acid cycle and also reveal the impairment of fatty acid beta-oxidation in liver mitochondria of such treated mice.
authors.affiliation: Biological Chemistry, Biomedical Sciences Division, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Sir Alexander Fleming Building, South Kensington, London SW7 2AZ, United Kingdom.
authors.forename: Muireann
authors.initials: M
authors.lastname: Coen
authors.forename: Eva M
authors.initials: EM
authors.lastname: Lenz
authors.forename: Jeremy K
authors.initials: JK
authors.lastname: Nicholson
authors.forename: Ian D
authors.initials: ID
authors.lastname: Wilson
authors.forename: Francois
authors.initials: F
authors.lastname: Pognan
authors.forename: John C
authors.initials: JC
authors.lastname: Lindon
mesh_terms: D000082:Acetaminophen / Q000097:blood / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000032:analysis / Q000378:metabolism; D006003:Glycogen / Q000032:analysis / Q000378:metabolism; D050356:Lipid Metabolism; D008055:Lipids / Q000032:analysis; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008110:Liver Extracts / Q000737:chemistry; D008297:Male; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods*; D025341:Principal Component Analysis; D013997:Time Factors
chemical_list: D008055:Lipids; D008110:Liver Extracts; D000082:Acetaminophen; D006003:Glycogen; D005947:Glucose