title: 1H NMR-based metabonomics approach in a rat model of acute liver injury and regeneration induced by CCl4 administration.
abstract: The administration of carbon tetrachloride (CCl(4)) has been established as a model of toxin-induced acute and chronic liver injury. In the present study, we investigate the progression of the biochemical response to acute CCl(4)-induced liver injury, capturing metabolic variations during both toxic insult and regeneration using NMR-based metabonomic analysis of liver tissue and plasma. A single dose of CCl(4) (1 mL/kg BW) was intraperitoneally administered to male Wister rats sacrificed every 12h up to 72 h post treatment, while healthy animals served as controls. Acquired (1)H NMR spectra of liver tissue extracts and plasma samples were explored with multivariate analysis and the resulted models were correlated with conventional biochemical and histopathological indices of toxicity for monitoring the progression of experimental injury. The metabonomic analysis resulted in discrimination between the subjects under toxic insult (up to 36 h) and those at the regenerative phase (peaked at 48 h). At 72 h normalization of liver's pathology similar to the controls group was apparent. Principal component analysis (PCA) trajectories highlighted the time points of the greater degree of toxic insult and the regenerative state. A number of metabolites such as glucose, lactate, choline, formate exhibited variations suggesting CCl(4) induced impairment in essential biochemical pathways as energy metabolism, lipid biosynthesis and transmethylation reactions. The latter provides new evidence of B12 and folate pathways deficiency, indicative of new mechanistic implications possibly by direct inhibition of B12 dependent enzymes by the chlorinated radicals of CCl(4) metabolism.
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of Athens, Panepistimioupolis Zografou, 15771 Athens, Greece.
authors.forename: Athina
authors.initials: A
authors.lastname: Zira
authors.forename: Sarantos
authors.initials: S
authors.lastname: Kostidis
authors.forename: Stamatios
authors.initials: S
authors.lastname: Theocharis
authors.forename: Fragiska
authors.initials: F
authors.lastname: Sigala
authors.forename: Søren Balling
authors.initials: SB
authors.lastname: Engelsen
authors.forename: Ioanna
authors.initials: I
authors.lastname: Andreadou
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Mikros
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced* / Q000503:physiopathology; D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity*; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects; D005492:Folic Acid / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008055:Lipids / Q000096:biosynthesis; D008115:Liver Regeneration / Q000502:physiology*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008297:Male; D055432:Metabolomics / Q000379:methods*; D051379:Mice; D015999:Multivariate Analysis; D025341:Principal Component Analysis; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014805:Vitamin B 12 / Q000378:metabolism
chemical_list: D008055:Lipids; D005492:Folic Acid; D002251:Carbon Tetrachloride; D014805:Vitamin B 12