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Sensitivity of 1H NMR analysis of rat urine in relation to toxicometabonomics. Part I: Dose-dependent toxic fffects of Bromobenzene and paracetamol

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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. · Zuylen, C.T. van · Tas, A.C. · Nesselrooij, J.H.J. van · Vogels, J.T.W.E.
Institution: TNO Kwaliteit van Leven
Source:Toxicological Sciences, 1, 98, 271-285
Identifier: 240037
doi: doi:10.1093/toxsci/kfm076
Keywords: Biology · Analytical research · Biomarkers · Bromobenzene · Hepatotoxicity · Metabonomics · Necrosis · Paracetamol · Urinalysis · alanine aminotransferase · aspartate aminotransferase · biological marker · bromobenzene · paracetamol · alanine aminotransferase blood level · animal experiment · animal tissue · article · aspartate aminotransferase blood level · clinical chemistry · controlled study · diagnostic accuracy · diagnostic value · dose response · drug blood level · drug urine level · early diagnosis · histopathology · intermethod comparison · liver dysfunction · liver necrosis · liver toxicity · male · non invasive measurement · nonhuman · pattern recognition · principal component analysis · proton nuclear magnetic resonance · rat · sensitivity analysis · spectrometer · urinalysis · Acetaminophen · Alanine Transaminase · Analgesics, Non-Narcotic · Animals · Aspartate Aminotransferases · Bromobenzenes · Dose-Response Relationship, Drug · Hepatitis, Toxic · Kidney · Liver · Magnetic Resonance Spectroscopy · Necrosis · Principal Component Analysis · Rats · Rattus


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.