Uniform procedure of 1H NMR analysis of rat urine and toxicometabonomics Part II : Comparison of NMR profiles classification of hepatotoxicity
article
A procedure of nuclear magnetic resonance (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 nontoxic control compound (mianserine) in rats. The toxic compounds are expected to induce necrosis (bromobenzene, paracetamol, carbon tetrachloride, iproniazid, isoniazid, thioacetamide), cholestasis (α-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 first and second 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 preselected 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. © The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.
Topics
Analytical researchCholestasisHepatotoxicityMetabonomicsNecrosisNMRSteatosisUrinalysis1 naphthyl isothiocyanatebiological markerbromobenzenecarbon tetrachloridechlorpromazineethinylestradiolibuprofeniproniazidisoniazidmethyltestosteronemianserinparacetamolphenobarbitalplacebotetracyclinethioacetamideanimal experimentanimal tissuearticlecontrolled studydiagnostic accuracydiagnostic valuedrug blood leveldrug urine levelearly diagnosisfatty liverhistopathologyintermethod comparisonintrahepatic cholestasisliver necrosisliver toxicitymalenonhumanpattern recognitionpredictionprincipal component analysisproton nuclear magnetic resonanceraturinalysisAnimalsBiological MarkersCholestasisFatty LiverHepatitis, ToxicLiverMagnetic Resonance SpectroscopyMaleNecrosisPattern Recognition, AutomatedPrincipal Component AnalysisRatsRats, WistarUrineAnimaliaRattus
TNO Identifier
240069
ISSN
10966080
Source
Toxicological Sciences, 98(1), pp. 286-297.
Pages
286-297
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