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ToxSci Advance Access originally published online on April 9, 2007
Toxicological Sciences 2007 98(1):271-285; doi:10.1093/toxsci/kfm076
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Sensitivity of 1H NMR Analysis of Rat Urine in Relation to Toxicometabonomics. Part I: Dose-Dependent Toxic Effects of Bromobenzene and Paracetamol

Willem G. E. J. Schoonen*,1, Cathelijne P. A. M. Kloks{dagger}, Jan-Peter H. T. M. Ploemen{ddagger}, G. Jean Horbach*, Martin J. Smit*, Pieter Zandberg*, Jan-Remt Mellema{dagger}, Carol Thijssen-van Zuylen{dagger}, Albert C. Tas§, Joop H. J. van Nesselrooij§ and Jack T. W. E. Vogels§

* Department of Pharmacology, N.V. Organon, Molenstraat 110, 5340 BH Oss, The Netherlands {dagger} Department of Medicinal Chemistry, N.V. Organon, Molenstraat 110, 5340 BH Oss, The Netherlands {ddagger} Department of Toxicology and Drug Disposition, N.V. Organon, Molenstraat 110, 5340 BH Oss, The Netherlands § Department of Analytical Research, TNO Quality of Life, Utrechtseweg 48, PO Box 360, 3700 AJ Zeist, The Netherlands

1 To whom correspondence should be addressed. Fax: +31-412-663532. E-mail: willem.schoonen{at}organon.com.

Received October 23, 2006; accepted March 22, 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.

Key Words: metabonomics; urinalysis; hepatotoxicity; bromobenzene; paracetamol; necrosis; biomarkers.


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