title: Acute liver acetaminophen toxicity in rabbits and the use of antidotes: a metabonomic approach in serum.
abstract: The metabonomic approach has been widely used in toxicology to investigate mechanisms of toxicity. In the present study alterations in the metabolic profiles, monitored by (1)H-NMR spectroscopy, on serum samples in acetaminophen (APAP)-induced liver injury in rabbits were examined. Furthermore, the effect of the established antidote N-acetylcysteine (NAC) and the proposed antidotes silybinin (SIL), cimetidine (CIM) and SIL/CIM was also investigated. A single dose of APAP (2 g kg(-1) b.w., i.g.) was administered to rabbits and APAP combined with the antidotes SIL, CIM and NAC. Animals were sacrificed at 24 h post-APAP treatment. Healthy untreated animals served as controls. (1)H-NMR spectra of serum samples were acquired and underwent principal component analysis (PCA). Acute liver injury was verified by histopathological examination and the alterations of serum biochemical enzymes AST and ALT. (1)H-NMR spectroscopy revealed variations in the serum metabolic profile of APAP-intoxicated rabbits compared with controls. Co-administration of APAP with NAC, CIM and SIL + CIM seems to ameliorate the metabolic profile of animals compared with simply APAP-treated ones. In this study, the model of APAPinduced liver injury was successfully described using the (1)H-NMR based metabonomic approach in serum. Furthermore, the use of antidotes that reduced the toxic insult was also recorded using this technique. The combination of NMR spectroscopy and PCA is a rapid methodology, capable of detecting alterations in the metabolic profile, and produces adequate models that could be used for the characterization of unknown samples, both experimental and clinical, reinforcing its future use in clinical settings.
authors.affiliation: Department of Forensic Medicine and Toxicology, University of Athens, Greece.
authors.forename: Athina
authors.initials: A
authors.lastname: Zira
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Mikros
authors.forename: Konstantina
authors.initials: K
authors.lastname: Giannioti
authors.forename: Panagiota
authors.initials: P
authors.lastname: Galanopoulou
authors.forename: Apostolos
authors.initials: A
authors.lastname: Papalois
authors.forename: Charis
authors.initials: C
authors.lastname: Liapi
authors.forename: Stamatios
authors.initials: S
authors.lastname: Theocharis
mesh_terms: D000082:Acetaminophen / Q000493:pharmacokinetics / Q000633:toxicity*; D000111:Acetylcysteine / Q000008:administration & dosage / Q000627:therapeutic use; D000208:Acute Disease; D000410:Alanine Transaminase / Q000097:blood*; D000818:Animals; D000931:Antidotes / Q000008:administration & dosage / Q000627:therapeutic use*; D001219:Aspartate Aminotransferases / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D002927:Cimetidine / Q000008:administration & dosage / Q000627:therapeutic use; D004195:Disease Models, Animal; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D011817:Rabbits; D000077385:Silybin; D012838:Silymarin / Q000008:administration & dosage / Q000627:therapeutic use
chemical_list: D000931:Antidotes; D015415:Biomarkers; D012838:Silymarin; D000082:Acetaminophen; D000077385:Silybin; D002927:Cimetidine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000111:Acetylcysteine