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Uniform procedure of 1H NMR analysis of rat urine and toxicometabonomics Part II : Comparison of NMR profiles classification of hepatotoxicity

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Author: Schoonen, W.G.E.J. · Kloks, C.P.A.M. · Ploemen, J.-P.H.T.M. · Smit, M.J. · Zandberg, P. · Horbach, G.J. · Mellema, J.-R. · Zuylen, C.T. van · Tas, A.C. · Nesselrooij, J.H.J. van · Vogels, J.T.W.E.
Institution: TNO Kwaliteit van Leven
Source:Toxicological Sciences, 1, 98, 286-297
Identifier: 240069
doi: doi:10.1093/toxsci/kfm077
Keywords: Biology · Analytical research · Cholestasis · Hepatotoxicity · Metabonomics · Necrosis · NMR · Steatosis · Urinalysis · 1 naphthyl isothiocyanate · biological marker · bromobenzene · carbon tetrachloride · chlorpromazine · ethinylestradiol · ibuprofen · iproniazid · isoniazid · methyltestosterone · mianserin · paracetamol · phenobarbital · placebo · tetracycline · thioacetamide · animal experiment · animal tissue · article · controlled study · diagnostic accuracy · diagnostic value · drug blood level · drug urine level · early diagnosis · fatty liver · histopathology · intermethod comparison · intrahepatic cholestasis · liver necrosis · liver toxicity · male · nonhuman · pattern recognition · prediction · principal component analysis · proton nuclear magnetic resonance · rat · urinalysis · Animals · Biological Markers · Cholestasis · Fatty Liver · Hepatitis, Toxic · Liver · Magnetic Resonance Spectroscopy · Male · Necrosis · Pattern Recognition, Automated · Principal Component Analysis · Rats · Rats, Wistar · Urine · Animalia · Rattus


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.