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Metabolomics and biomarker discovery: NMR spectral data of urine and hepatotoxicity by carbon tetrachloride, acetaminophen, and d-galactosamine in rats

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Abstract

The primary objective of this study was to discover biomarkers which are correlated with hepatotoxicity induced by chemicals using 1H NMR spectral data of urine. A procedure of nuclear magnetic resonance (NMR) urinalysis using pattern recognition was proposed for early screening of the hepatotoxicity of CCl4, acetaminophen (AAP), and d-galactosamine (GalN) in rats. The hepatotoxic compounds were expected to induce necrosis in hepatocytes. This was confirmed through blood biochemistry and histopathology. CCl4 (1 ml/kg, po) or GalN (0.8 g/kg, ip) was single administered to Sprague–Dawley (S–D) rats and urine was collected every 24 h. Animals were sacrificed 24 h or 48 h post-dosing. AAP (2 g/kg, po) was administered for 2 days and then the animals were sacrificed 24 h after the last treatment. NMR spectroscopy revealed evidently different clustering between control groups and hepatotoxicant treatment groups in global metabolic profilings as indicated by partial least square (PLS)-discrimination analysis (DA). In targeted profilings, endogenous metabolites of allantoin, citrate, taurine, 2-oxoglutarate, acetate, lactate, phenylacetyl glycine, succinate, phenylacetate, 1-methylnicotinamide, hippurate, and benzoate were selected as putative biomarkers for hepatoxicity by CCl4, AAP, and GalN. Comparison of our rat 1H NMR PLS-DA data with histopathological changes suggests that 1H NMR urinalysis can be used to predict hepatotoxicity induced by CCl4, AAP, and GalN.

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Acknowledgments

This research was supported by a grant (07151KFDA626) from Korea Food & Drug Administration in 2007. The authors thank Dr. Geum-Sook Hwang for technical assistance of NMR urinalysis at Korea Basic Science Institute (Seoul, Korea).

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  1. Department of Pharmacology, National Institute of Toxicological Research, Korea Food and Drug Administration, 5-Nokbun-dong, Eunpyung-gu, Seoul, 122-704, South Korea

    Kyu-Bong Kim, Myeon Woo Chung, So Young Um, Ji Seon Oh, Seon Hwa Kim, Mi Ae Na, Hye Young Oh & Ki Hwan Choi

  2. Department of Toxicology, National Institute of Toxicological Research, Korea Food and Drug Administration, 5-Nokbun-dong, Eunpyung-gu, Seoul, 122-704, South Korea

    Wan-Seob Cho

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  1. Kyu-Bong Kim
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  2. Myeon Woo Chung
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Kim, KB., Chung, M.W., Um, S.Y. et al. Metabolomics and biomarker discovery: NMR spectral data of urine and hepatotoxicity by carbon tetrachloride, acetaminophen, and d-galactosamine in rats. Metabolomics 4, 377–392 (2008). https://doi.org/10.1007/s11306-008-0131-5

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