Skip Navigation



ToxSci Advance Access published online on April 9, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm076
This Article
Right arrow Advance Access manuscript (PDF) Freely available
Right arrow Supplementary Data
Right arrow All Versions of this Article:
98/1/271    most recent
kfm076v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Schoonen, W.
Right arrow Articles by Vogels, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Schoonen, W.
Right arrow Articles by Vogels, J.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 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 Toxico-Metabonomics. Part I: Dose Dependent Toxic Effects of Bromobenzene and Paracetamol

WGEJ Schoonen1, CPAM Kloks2, J-PHTM Ploemen3, GJMJ Horbach1, MJ Smit1, P Zandberg1, JR Mellema2, C Thijssen-van Zuylen2, AC Tas4, JHJ van Nesselrooij4 and JTWE Vogels4

1 Department of Pharmacology, N.V. Organon, Molenstraat 110, 5340 BH Oss, The Netherlands 2 Department of Medicinal Chemistry, N.V. Organon, Molenstraat 110, 5340 BH Oss, The Netherlands 3 Department of Toxicology and Drug Disposition, N.V. Organon, Molenstraat 110, 5340 BH Oss, The Netherlands 4 Department of Food and Food supplements, TNO Food and Nutrition Research, Utrechtseweg 48, PO Box 360, 3700 AJ Zeist, The Netherlands

E-mails: willem.schoonen{at}organon.com, vannesselrooij{at}voeding.tno.nl Tel: 31-412-662919 31-30-6944432 Fax: 31-412-663532 31-30-6944077

Received October 23, 2006; revision received March 8, 2007; accepted March 22, 2007


  Abstract

1H NMR spectroscopy of rat urine in combination with pattern recognition analysis was evaluated for early non-invasive 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 1,800 mg/kg, respectively. The sensitivity of the proposed method to detect changes in the NMR spectra 24 and 48 hrs 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 (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.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.