Sensitivity of 1H NMR analysis of rat urine in relation to toxicometabonomics. Part I: Dose-dependent toxic fffects of Bromobenzene and paracetamol
van Zuylen, C.T.
van Nesselrooij, J.H.J.
TNO Kwaliteit van Leven
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.
To reference this document use:
alanine aminotransferase blood level
aspartate aminotransferase blood level
drug blood level
drug urine level
non invasive measurement
principal component analysis
proton nuclear magnetic resonance
Dose-Response Relationship, Drug
Magnetic Resonance Spectroscopy
Principal Component Analysis
Toxicological Sciences, 98 (1), 271-285