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ToxSci Advance Access published online on April 9, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm077
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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

Uniform Procedure of 1H NMR Analysis of Rat Urine and Toxico-Metabonomics. Part II: Comparison of NMR Profiles For Classification of Hepatotoxicity

WGEJ Schoonen1, CPAM Kloks2, J-PHTM Ploemen3, MJ Smit1, P Zandberg1, GJMJ Horbach1, 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 Medical 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 Analytical Research, TNO Quality of Life, 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 13, 2007; accepted March 22, 2007


  Abstract

A procedure of NMR urinalysis using pattern recognition is proposed for early detection of toxicity of investigational compounds in rats. The method is applied to detect toxicity upon administration of 13 toxic reference compounds and one non-toxic control compound (mianserine) in rats. The toxic compounds are expected to induce necrosis (bromobenzene, paracetamol, carbon tetrachloride, iproniazid, isoniazid, thioacetamide), cholestasis ({alpha}-naphthylisothiocyanate (ANIT), chlorpromazine, ethinylestradiol, methyltestosterone, ibuprofen) or steatosis (phenobarbital, tetracycline). Animals were treated daily for 2 or 4 days except for paracetamol and bromobenzene (1 and 2 days) and carbon tetrachloride (1 day only). Urine was collected 24 h after the 1st and 2nd treatment. The animals were sacrificed 24 h after the last treatment and NMR data were compared with liver histopathology as well as blood and urine biochemistry.

Pathology and biochemistry showed marked toxicity in the liver at high doses of bromobenzene, paracetamol, carbon tetrachloride, ANIT, and ibuprofen. Thioacetamide and chlorpromazine showed less extensive changes, while the influences of iproniazid, isoniazid, phenobarbital, ethinylestradiol and tetracycline on the toxic parameters were marginal or for methyltestosterone and mianserine negligible. NMR spectroscopy revealed significant changes upon dosing in 88 NMR biomarker signals pre-selected with the Procrustus Rotation method on principal component discriminant analysis (PCDA) plots. Further evaluation of the specific changes led to the identification of biomarker patterns for the specific types of liver toxicity. Comparison of our rat NMR-PCDA data with histopathological changes reported in humans and/or rats suggests that rat NMR urinalysis can be used to predict hepatotoxicity.

Key Words: metabonomics; urinalysis; hepatotoxicity; necrosis; cholestasis; steatosis; NMR.


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