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
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
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