Print Email Facebook Twitter Sensitivity of 1H NMR analysis of rat urine in relation to toxicometabonomics. Part I: Dose-dependent toxic fffects of Bromobenzene and paracetamol Title Sensitivity of 1H NMR analysis of rat urine in relation to toxicometabonomics. Part I: Dose-dependent toxic fffects of Bromobenzene and paracetamol Author Schoonen, W.G.E.J. Kloks, C.P.A.M. Ploemen, J.P.H.T.M. Horbach, G.J. Smit, M.J. Zandberg, P. Mellema, J.R. van Zuylen, C.T. Tas, A.C. van Nesselrooij, J.H.J. Vogels, J.T.W.E. TNO Kwaliteit van Leven Publication year 2007 Abstract 1H nuclear magnetic resonance (NMR) spectroscopy of rat urine in combination with pattern recognition analysis was evaluated for early noninvasive detection of toxicity of investigational chemical entities. Bromobenzene (B) and paracetamol (P) were administered at five single oral dosages between 2 and 500 mg/kg and between 6 and 1800 mg/kg, respectively. The sensitivity of the proposed method to detect changes in the NMR spectra 24 and 48 h after single dosing was compared with histopathology and biochemical parameters in plasma and urine. Both B and P applied at the highest dosages induced liver necrosis and markedly increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) plasma levels. At dosages of 125 mg/kg B and 450 mg/kg P, liver necrosis and changes in AST and ALT were less pronounced, while at lower dose levels these effects could not be detected. Changes in kidney pathology or standard urine biochemistry were not observed at any of these dosages. Evaluation of the total NMR dataset showed 80 signals to be sensitive for B and P dosing. Principal component analysis on the reduced dataset revealed that NMR spectra were significantly different at dosages above 8 mg/kg (B) and 110 mg/kg (P) at both sampling times. This implies a 4- to 16-fold increased sensitivity of NMR versus histopathology and clinical chemistry in recognizing early events of liver toxicity. © The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. Subject BiologyAnalytical researchBiomarkersBromobenzeneHepatotoxicityMetabonomicsNecrosisParacetamolUrinalysisalanine aminotransferaseaspartate aminotransferasebiological markerbromobenzeneparacetamolalanine aminotransferase blood levelanimal experimentanimal tissuearticleaspartate aminotransferase blood levelclinical chemistrycontrolled studydiagnostic accuracydiagnostic valuedose responsedrug blood leveldrug urine levelearly diagnosishistopathologyintermethod comparisonliver dysfunctionliver necrosisliver toxicitymalenon invasive measurementnonhumanpattern recognitionprincipal component analysisproton nuclear magnetic resonanceratsensitivity analysisspectrometerurinalysisAcetaminophenAlanine TransaminaseAnalgesics, Non-NarcoticAnimalsAspartate AminotransferasesBromobenzenesDose-Response Relationship, DrugHepatitis, ToxicKidneyLiverMagnetic Resonance SpectroscopyNecrosisPrincipal Component AnalysisRatsRattus To reference this document use: http://resolver.tudelft.nl/uuid:b8496818-4e3b-40ae-86f3-2e60f4c3b8a8 DOI https://doi.org/10.1093/toxsci/kfm076 TNO identifier 240037 ISSN 1096-6080 Source Toxicological Sciences, 98 (1), 271-285 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.