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Metabolomic profiling of biomarkers of liver X receptor-induced toxicity in mouse liver tissue

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Abstract

Methods based on matrix-assisted laser desorption/ionisation mass spectrometry (MALDI-MS), liquid chromatography coupled to an LTQ-Orbitrap mass spectrometer (LC-MS) and gas chromatography-mass spectrometry (GC-MS) were used to investigate changes in the small molecule profiles of mouse liver in response to administration of an LXR agonist. Mice were treated with either 0.3 mg/kg, 1 mg/kg, 10 mg/kg, 30 mg/kg or 60 mg/kg of an LXR test compound or saline (control) once daily, over a 5 day period, to investigate the effects of the drug on metabolism in the liver. It was possible to detect triacylglycerol accumulation in the livers of animals treated with the drug, even at the lowest concentrations using, in the first instance, MALDI MS. There was also an increase in the relative degree of triacylglycerol saturation in the drug-treated samples. Changes in the profiles of phosphatidylcholine lipids were also observed. The changes in lipid profiles were also confirmed by LC-MS and GC-MS, the latter revealing a large increase in the level of the free fatty acid oleic acid (C18:1) in the treated samples. All of the changes were dose-related. Polar metabolites in the samples were analysed by hydrophilic interaction (HILIC) chromatography in combination with an LTQ-Orbitrap mass spectrometer. There were many changes in the metabolite profiles, some of which might simply be related to generalised toxicity. The clearest marker compounds, which showed very marked changes with dose, were methylglutaryl carnitine (MGC) and hydroxymethylglutaryl carnitine (HMGC). Another marker of some interest was uridine diphosphate N-acetylglucosamine (UNGA).

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References

  • Altmaier, E., Ramsay, S. L., Graber, A., Mewes, H. W., Weinberger, K. M., & Suhre, K. (2008). Bioinformatics analysis of targeted metabolomics—Uncovering old and new tales of diabetic mice under medication. Endocrinology, 149, 3478–3489.

    CAS  PubMed  Google Scholar 

  • Anthonisen, E. H., Berven, L., Holm, S., Nygard, M., Nebb, H. I., & Gronning-Wang, L. M. (2010). Nuclear receptor liver X receptor is O-GlcNAc-modified in response to glucose. Journal of Biological Chemistry, 285, 1607–1615.

    CAS  PubMed  Google Scholar 

  • Bajad, S. U., Lu, W., Kimball, E. H., Yuan, J., Peterson, C., & Rabinowitz, J. D. (2006). Separation and quantitation of water soluble cellular metabolites by hydrophilic interaction chromatography-tandem mass spectrometry. Journal of Chromatography. A, 1125, 76–88.

    CAS  PubMed  Google Scholar 

  • Bao, Y., Zhao, T., Wang, X., Qiu, Y., Su, M., & Jia, W. (2009). Metabonomic variations in the drug-treated type 2 diabetes mellitus patients and healthy volunteers. Journal of Proteome Research, 8, 1623–1630.

    CAS  PubMed  Google Scholar 

  • Beger, R. D., Hansen, D. K., Schnackenberg, L. K., Cross, B. M., Fatollahi, J. J., Lagunero, F. T., et al. (2009). Single valproic acid treatment inhibits glycogen and RNA ribose turnover while disrupting glucose-derived cholesterol synthesis in liver as revealed by the [U-C(6)]-d-glucose tracer in mice. Metabolomics, 5, 336–345.

    CAS  PubMed  Google Scholar 

  • Beger, R. D., Sun, J., & Schnackenberg, L. K. (2010). Metabolomics approaches for discovering biomarkers of drug-induced hepatotoxicity and nephrotoxicity. Toxicology and Applied Pharmacology, 243, 154–166.

    CAS  PubMed  Google Scholar 

  • Benabdellah, F., Touboul, D., Brunelle, A., & Laprevote, O. (2009). In situ primary metabolites localization on a rat brain section by chemical mass spectrometry imaging. Analytical Chemistry, 81, 5557–5560.

    CAS  PubMed  Google Scholar 

  • Bollard, M. E., Contel, N. R., Ebbels, T. M., Smith, L., Beckonert, O., Cantor, G. H., et al. (2010). NMR-based metabolic profiling identifies biomarkers of liver regeneration following partial hepatectomy in the rat. Journal of Proteome Research, 9, 59–69.

    CAS  PubMed  Google Scholar 

  • Calvano, C. D., Zambonin, C. G., & Jensen, O. N. (2008). Assessment of lectin and HILIC based enrichment protocols for characterization of serum glycoproteins by mass spectrometry. Journal of Proteomics, 71, 304–317.

    CAS  PubMed  Google Scholar 

  • Cha, J. Y., & Repa, J. J. (2007). The liver X receptor (LXR) and hepatic lipogenesis. The carbohydrate-response element-binding protein is a target gene of LXR. Journal of Biological Chemistry, 282, 743–751.

    CAS  PubMed  Google Scholar 

  • Chen, C., Krausz, K. W., Shah, Y. M., Idle, J. R., & Gonzalez, F. J. (2009). Serum metabolomics reveals irreversible inhibition of fatty acid beta-oxidation through the suppression of PPARalpha activation as a contributing mechanism of acetaminophen-induced hepatotoxicity. Chemical Research in Toxicology, 22, 699–707.

    PubMed  Google Scholar 

  • Christie, W. W. (2003). Lipid analysis: Isolation, separation. Identification & structural analysis of lipids. Bridgwater, UK: The Oily Press.

    Google Scholar 

  • Coen, M., Hong, Y. S., Cloarec, O., Rhode, C. M., Reily, M. D., Robertson, D. G., et al. (2007). Heteronuclear 1H-31P statistical total correlation NMR spectroscopy of intact liver for metabolic biomarker assignment: Application to galactosamine-induced hepatotoxicity. Analytical Chemistry, 79, 8956–8966.

    CAS  PubMed  Google Scholar 

  • Coen, M., Lenz, E. M., Nicholson, J. K., Wilson, I. D., Pognan, F., & Lindon, J. C. (2003). An integrated metabonomic investigation of acetaminophen toxicity in the mouse using NMR spectroscopy. Chemical Research in Toxicology, 16, 295–303.

    CAS  PubMed  Google Scholar 

  • Coen, M., Wilson, I. D., Nicholson, J. K., Tang, H., & Lindon, J. C. (2004). Probing molecular dynamics in chromatographic systems using high-resolution 1H magic-angle-spinning NMR spectroscopy: Interaction between p-Xylene and C18-bonded silica. Analytical Chemistry, 76, 3023–3028.

    CAS  PubMed  Google Scholar 

  • Crockford, D. J., Keun, H. C., Smith, L. M., Holmes, E., & Nicholson, J. K. (2005). Curve-fitting method for direct quantitation of compounds in complex biological mixtures using 1H NMR: Application in metabonomic toxicology studies. Analytical Chemistry, 77, 4556–4562.

    CAS  PubMed  Google Scholar 

  • Cubbon, S., Bradbury, T., Wilson, J., & Thomas-Oates, J. (2007). Hydrophilic interaction chromatography for mass spectrometric metabonomic studies of urine. Analytical Chemistry, 79, 8911–8918.

    CAS  PubMed  Google Scholar 

  • Dettmer, K., Aronov, P. A., & Hammock, B. D. (2007). Mass spectrometry-based metabolomics. Mass Spectrometry Reviews, 26, 51–78.

    CAS  PubMed  Google Scholar 

  • Dumas, M. E., Canlet, C., Andre, F., Vercauteren, J., & Paris, A. (2002). Metabonomic assessment of physiological disruptions using 1H-13C HMBC-NMR spectroscopy combined with pattern recognition procedures performed on filtered variables. Analytical Chemistry, 74, 2261–2273.

    CAS  PubMed  Google Scholar 

  • Dunn, W. B., Bailey, N. J., & Johnson, H. E. (2005). Measuring the metabolome: Current analytical technologies. Analyst, 130, 606–625.

    CAS  PubMed  Google Scholar 

  • Dunn, W. B., & Ellis, D. I. (2005). Metabolomics: Current analytical platforms and methodologies. TrAC Trends in Analytical Chemistry, 24, 285–294.

    CAS  Google Scholar 

  • Ebbels, T. M., Keun, H. C., Beckonert, O. P., Bollard, M. E., Lindon, J. C., Holmes, E., et al. (2007). Prediction and classification of drug toxicity using probabilistic modeling of temporal metabolic data: The consortium on metabonomic toxicology screening approach. Journal of Proteome Research, 6, 4407–4422.

    CAS  PubMed  Google Scholar 

  • Edwards, J. L., & Kennedy, R. T. (2005). Metabolomic analysis of eukaryotic tissue and prokaryotes using negative mode MALDI time-of-flight mass spectrometry. Analytical Chemistry, 77, 2201–2209.

    CAS  PubMed  Google Scholar 

  • Eiris, J., Ribes, A., Fernandez-Prieto, R., Rodriguez-Garcia, J., Rodriguez-Segade, S., & Castro-Gago, M. (1998). 3-hydroxy-3-methylglutaric aciduria and recurrent Reye-like syndrome. Revista de neurologia, 26, 911–914.

    CAS  PubMed  Google Scholar 

  • Fahy, E., Subramaniam, S., Brown, H. A., Glass, C. K., Merrill, A. H., Jr., Murphy, R. C., et al. (2005). A comprehensive classification system for lipids. Journal of Lipid Research, 46, 839–861.

    CAS  PubMed  Google Scholar 

  • Ferrara, C. T., Wang, P., Neto, E. C., Stevens, R. D., Bain, J. R., Wenner, B. R., et al. (2008). Genetic networks of liver metabolism revealed by integration of metabolic and transcriptional profiling. PLoS Genet, 4, e1000034.

    PubMed  Google Scholar 

  • Fievet, C., & Staels, B. (2009). Liver X receptor modulators: Effects on lipid metabolism and potential use in the treatment of atherosclerosis. Biochemical Pharmacology, 77, 1316–1327.

    CAS  PubMed  Google Scholar 

  • Garrod, S., Bollard, M. E., Nicholls, A. W., Connor, S. C., Connelly, J., Nicholson, J. K., et al. (2005). Integrated metabonomic analysis of the multiorgan effects of hydrazine toxicity in the rat. Chemical Research in Toxicology, 18, 115–122.

    CAS  PubMed  Google Scholar 

  • Gika, H. G., Theodoridis, G. A., & Wilson, I. D. (2008). Hydrophilic interaction and reversed-phase ultra-performance liquid chromatography TOF-MS for metabonomic analysis of Zucker rat urine. Journal of Separation Science, 31, 1598–1608.

    CAS  PubMed  Google Scholar 

  • Grefhorst, A., Elzinga, B. M., Voshol, P. J., Plosch, T., Kok, T., Bloks, V. W., et al. (2002). Stimulation of lipogenesis by pharmacological activation of the liver X receptor leads to production of large, triglyceride-rich very low density lipoprotein particles. Journal of Biological Chemistry, 277, 34182–34190.

    CAS  PubMed  Google Scholar 

  • Griffin, J. L. (2003). Metabonomics: NMR spectroscopy and pattern recognition analysis of body fluids and tissues for characterisation of xenobiotic toxicity and disease diagnosis. Current Opinion in Chemical Biology, 7, 648–654.

    CAS  PubMed  Google Scholar 

  • Griffin, J. L., Blenkiron, C., Valonen, P. K., Caldas, C., & Kauppinen, R. A. (2006). High-resolution magic angle spinning 1H NMR spectroscopy and reverse transcription-PCR analysis of apoptosis in a rat glioma. Analytical Chemistry, 78, 1546–1552.

    CAS  PubMed  Google Scholar 

  • Griffin, J. L., & Bollard, M. E. (2004). Metabonomics: Its potential as a tool in toxicology for safety assessment and data integration. Current Drug Metabolism, 5, 389–398.

    CAS  PubMed  Google Scholar 

  • Griffin, J. L., Pole, J. C., Nicholson, J. K., & Carmichael, P. L. (2003). Cellular environment of metabolites and a metabonomic study of tamoxifen in endometrial cells using gradient high resolution magic angle spinning 1H NMR spectroscopy. Biochimica et Biophysica Acta, 1619, 151–158.

    CAS  PubMed  Google Scholar 

  • Hegardt, F. G. (1999). Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase: A control enzyme in ketogenesis. Biochemical Journal, 338(Pt 3), 569–582.

    CAS  PubMed  Google Scholar 

  • Heijne, W. H., Lamers, R. J., van Bladeren, P. J., Groten, J. P., van Nesselrooij, J. H., & van Ommen, B. (2005). Profiles of metabolites and gene expression in rats with chemically induced hepatic necrosis. Toxicologic Pathology, 33, 425–433.

    CAS  PubMed  Google Scholar 

  • Holmes, E., Bonner, F. W., Sweatman, B. C., Lindon, J. C., Beddell, C. R., Rahr, E., et al. (1992). Nuclear-magnetic-resonance spectroscopy and pattern-recognition analysis of the biochemical processes associated with the progression of and recovery from nephrotoxic lesions in the rat induced by Mercury(Ii) Chloride and 2-Bromoethanamine. Molecular Pharmacology, 42, 922–930.

    CAS  PubMed  Google Scholar 

  • Holmes, E., Tsang, T. M., & Tabrizi, S. J. (2006). The application of NMR-based metabonomics in neurological disorders. NeuroRx, 3, 358–372.

    CAS  PubMed  Google Scholar 

  • Hong, Y. S., Coen, M., Rhode, C. M., Reily, M. D., Robertson, D. G., Holmes, E., et al. (2009). Chemical shift calibration of 1H MAS NMR liver tissue spectra exemplified using a study of glycine protection of galactosamine toxicity. Magnetic Resonance in Chemistry, 47(1), S47–S53.

    CAS  PubMed  Google Scholar 

  • Hu, Q., Noll, R. J., Li, H., Makarov, A., Hardman, M., & Graham Cooks, R. (2005). The Orbitrap: A new mass spectrometer. Journal of Mass Spectrometry and Ion Physics, 40, 430–443.

    CAS  Google Scholar 

  • Idborg, H., Zamani, L., Edlund, P. O., Schuppe-Koistinen, I., & Jacobsson, S. P. (2005). Metabolic fingerprinting of rat urine by LC/MS Part 2. Data pretreatment methods for handling of complex data. Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences, 828, 14–20.

    CAS  PubMed  Google Scholar 

  • Idborg-Bjorkman, H., Edlund, P. O., Kvalheim, O. M., Schuppe-Koistinen, I., & Jacobsson, S. P. (2003). Screening of biomarkers in rat urine using LC/electrospray ionization-MS and two-way data analysis. Analytical Chemistry, 75, 4784–4792.

    PubMed  Google Scholar 

  • Ishihara, K., Katsutani, N., & Aoki, T. (2006). A metabonomics study of the hepatotoxicants galactosamine, methylene dianiline and clofibrate in rats. Basic & Clinical Pharmacology & Toxicology, 99, 251–260.

    CAS  Google Scholar 

  • Kamleh, A., Barrett, M. P., Wildridge, D., Burchmore, R. J., Scheltema, R. A., & Watson, D. G. (2008a). Metabolomic profiling using Orbitrap Fourier transform mass spectrometry with hydrophilic interaction chromatography: A method with wide applicability to analysis of biomolecules. Rapid Communications in Mass Spectrometry, 22, 1912–1918.

    CAS  PubMed  Google Scholar 

  • Kamleh, M. A., Dow, J. A., & Watson, D. G. (2009a). Applications of mass spectrometry in metabolomic studies of animal model and invertebrate systems. Briefings in Functional Genomics & Proteomics, 8, 28–48.

    CAS  Google Scholar 

  • Kamleh, M. A., Hobani, Y., Dow, J. A., & Watson, D. G. (2008b). Metabolomic profiling of Drosophila using liquid chromatography Fourier transform mass spectrometry. FEBS Letters, 582, 2916–2922.

    CAS  PubMed  Google Scholar 

  • Kamleh, M. A., Hobani, Y., Dow, J. A., Zheng, L., & Watson, D. G. (2009b). Towards a platform for the metabonomic profiling of different strains of Drosophila melanogaster using liquid chromatography-Fourier transform mass spectrometry. FEBS Journal, 276, 6798–6809.

    CAS  PubMed  Google Scholar 

  • Keun, H. C., Ebbels, T. M., Antti, H., Bollard, M. E., Beckonert, O., Schlotterbeck, G., et al. (2002). Analytical reproducibility in (1)H NMR-based metabonomic urinalysis. Chemical Research in Toxicology, 15, 1380–1386.

    CAS  PubMed  Google Scholar 

  • Kind, T., Tolstikov, V., Fiehn, O., & Weiss, R. H. (2007). A comprehensive urinary metabolomic approach for identifying kidney cancerr. Analytical Biochemistry, 363, 185–195.

    CAS  PubMed  Google Scholar 

  • Lafaye, A., Junot, C., Pereira, Y., Lagniel, G., Tabet, J. C., Ezan, E., et al. (2005a). Combined proteome and metabolite-profiling analyses reveal surprising insights into yeast sulfur metabolism. Journal of Biological Chemistry, 280, 24723–24730.

    CAS  PubMed  Google Scholar 

  • Lafaye, A., Junot, C., Ramounet-Le Gall, B., Fritsch, P., Tabet, J. C., & Ezan, E. (2003). Metabolite profiling in rat urine by liquid chromatography/electrospray ion trap mass spectrometry. Application to the study of heavy metal toxicity. Rapid Communications in Mass Spectrometry, 17, 2541–2549.

    CAS  PubMed  Google Scholar 

  • Lafaye, A., Labarre, J., Tabet, J. C., Ezan, E., & Junot, C. (2005b). Liquid chromatography-mass spectrometry and 15 N metabolic labeling for quantitative metabolic profiling. Analytical Chemistry, 77, 2026–2033.

    CAS  PubMed  Google Scholar 

  • Lay, J. O., Jr., Liyanage, R., Durham, B., & Brooks, J. (2006). Rapid characterization of edible oils by direct matrix-assisted laser desorption/ionization time-of-flight mass spectrometry analysis using triacylglycerols. Rapid Communications in Mass Spectrometry, 20, 952–958.

    CAS  PubMed  Google Scholar 

  • Lenz, E. M., Bright, J., Knight, R., Wilson, I. D., & Major, H. (2004a). Cyclosporin A-induced changes in endogenous metabolites in rat urine: A metabonomic investigation using high field 1H NMR spectroscopy, HPLC-TOF/MS and chemometrics. Journal of Pharmaceutical and Biomedical Analysis, 35, 599–608.

    CAS  PubMed  Google Scholar 

  • Lenz, E. M., Bright, J., Knight, R., Wilson, I. D., & Major, H. (2004b). A metabonomic investigation of the biochemical effects of mercuric chloride in the rat using 1H NMR and HPLC-TOF/MS: Time dependent changes in the urinary profile of endogenous metabolites as a result of nephrotoxicity. Analyst, 129, 535–541.

    CAS  PubMed  Google Scholar 

  • Lenz, E. M., & Wilson, I. D. (2007). Analytical strategies in metabonomics. Journal of Proteome Research, 6, 443–458.

    CAS  PubMed  Google Scholar 

  • Lewis, I. A., Schommer, S. C., Hodis, B., Robb, K. A., Tonelli, M., Westler, W. M., et al. (2007). Method for determining molar concentrations of metabolites in complex solutions from two-dimensional 1H-13C NMR spectra. Analytical Chemistry, 79, 9385–9390.

    CAS  PubMed  Google Scholar 

  • Lindon, J. C., Holmes, E., Bollard, M. E., Stanley, E. G., & Nicholson, J. K. (2004). Metabonomics technologies and their applications in physiological monitoring, drug safety assessment and disease diagnosis. Biomarkers, 9, 1–31.

    CAS  PubMed  Google Scholar 

  • Lindon, J. C., Holmes, E., & Nicholson, J. K. (2007). Metabonomics in pharmaceutical R&D. FEBS Journal, 274, 1140–1151.

    CAS  PubMed  Google Scholar 

  • Lindon, J. C., Keun, H. C., Ebbels, T. M., Pearce, J. M., Holmes, E., & Nicholson, J. K. (2005a). The Consortium for Metabonomic Toxicology (COMET): Aims, activities and achievements. Pharmacogenomics, 6, 691–699.

    CAS  PubMed  Google Scholar 

  • Lindon, J. C., Nicholson, J. K., Holmes, E., Antti, H., Bollard, M. E., Keun, H., et al. (2003). Contemporary issues in toxicology the role of metabonomics in toxicology and its evaluation by the COMET project. Toxicology and Applied Pharmacology, 187, 137–146.

    CAS  PubMed  Google Scholar 

  • Lindon, J. C., Nicholson, J. K., Holmes, E., Keun, H. C., Craig, A., Pearce, J. T., et al. (2005b). Summary recommendations for standardization and reporting of metabolic analyses. Nature Biotechnology, 23, 833–838.

    CAS  PubMed  Google Scholar 

  • Mortishire-Smith, R. J., Skiles, G. L., Lawrence, J. W., Spence, S., Nicholls, A. W., Johnson, B. A., et al. (2004). Use of metabonomics to identify impaired fatty acid metabolism as the mechanism of a drug-induced toxicity. Chemical Research in Toxicology, 17, 165–173.

    CAS  PubMed  Google Scholar 

  • Nicholson, J. K., Connelly, J., Lindon, J. C., & Holmes, E. (2002). Metabonomics: A platform for studying drug toxicity and gene function. Nature Reviews. Drug Discovery, 1, 153–161.

    CAS  PubMed  Google Scholar 

  • Nicholson, J., Keun, H., & Ebbels, T. (2007). COMET and the challenge of drug safety screening. Journal of Proteome Research, 6, 4098–4099.

    CAS  PubMed  Google Scholar 

  • Nordstrom, A., Want, E., Northen, T., Lehtio, J., & Siuzdak, G. (2008). Multiple ionization mass spectrometry strategy used to reveal the complexity of metabolomics. Analytical Chemistry, 80, 421–429.

    PubMed  Google Scholar 

  • Ohta, D., Kanaya, S., & Suzuki, H. (2010). Application of Fourier-transform ion cyclotron resonance mass spectrometry to metabolic profiling and metabolite identification. Current Opinion in Biotechnology, 21, 35–44.

    CAS  PubMed  Google Scholar 

  • Paek, I. B., Moon, Y., Ji, H. Y., Kim, H. H., Lee, H. W., Lee, Y. B., et al. (2004). Hydrophilic interaction liquid chromatography-tandem mass spectrometry for the determination of levosulpiride in human plasma. Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences, 809, 345–350.

    CAS  PubMed  Google Scholar 

  • Pasikanti, K. K., Ho, P. C., & Chan, E. C. (2008a). Gas chromatography/mass spectrometry in metabolic profiling of biological fluids. Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences, 871, 202–211.

    CAS  PubMed  Google Scholar 

  • Pasikanti, K. K., Ho, P. C., & Chan, E. C. (2008b). Development and validation of a gas chromatography/mass spectrometry metabonomic platform for the global profiling of urinary metabolites. Rapid Communications in Mass Spectrometry, 22, 2984–2992.

    CAS  PubMed  Google Scholar 

  • Picariello, G., Paduano, A., Sacchi, R., & Addeo, F. (2009). Maldi-tof mass spectrometry profiling of polar and nonpolar fractions in heated vegetable oils. Journal of Agriculture and Food Chemistry, 57, 5391–5400.

    CAS  Google Scholar 

  • Plumb, R. S., Granger, J. H., Stumpf, C. L., Johnson, K. A., Smith, B. W., Gaulitz, S., et al. (2005). A rapid screening approach to metabonomics using UPLC and oa-TOF mass spectrometry: Application to age, gender and diurnal variation in normal/Zucker obese rats and black, white and nude mice. Analyst, 130, 844–849.

    CAS  PubMed  Google Scholar 

  • Plumb, R., Granger, J., Stumpf, C., Wilson, I. D., Evans, J. A., & Lenz, E. M. (2003). Metabonomic analysis of mouse urine by liquid-chromatography-time of flight mass spectrometry (LC-TOFMS): Detection of strain, diurnal and gender differences. Analyst, 128, 819–823.

    CAS  PubMed  Google Scholar 

  • Plumb, R. S., Johnson, K. A., Rainville, P., Shockcor, J. P., Williams, R., Granger, J. H., et al. (2006). The detection of phenotypic differences in the metabolic plasma profile of three strains of Zucker rats at 20 weeks of age using ultra-performance liquid chromatography/orthogonal acceleration time-of-flight mass spectrometry. Rapid Communications in Mass Spectrometry, 20, 2800–2806.

    CAS  PubMed  Google Scholar 

  • Plumb, R. S., Jones, M. D., Rainville, P. D., & Nicholson, J. K. (2008). A rapid simple approach to screening pharmaceutical products using ultra-performance LC coupled to time-of-flight mass spectrometry and pattern recognition. Journal of Chromatographic Science, 46, 193–198.

    CAS  PubMed  Google Scholar 

  • Plumb, R. S., Rainville, P. D., Potts, W. B., III, Johnson, K. A., Gika, E., & Wilson, I. D. (2009). Application of ultra performance liquid chromatography-mass spectrometry to profiling rat and dog bile. Journal of Proteome Research, 8, 2495–2500.

    CAS  PubMed  Google Scholar 

  • Plumb, R. S., Stumpf, C. L., Gorenstein, M. V., Castro-Perez, J. M., Dear, G. J., Anthony, M., et al. (2002). Metabonomics: The use of electrospray mass spectrometry coupled to reversed-phase liquid chromatography shows potential for the screening of rat urine in drug development. Rapid Communications in Mass Spectrometry, 16, 1991–1996.

    CAS  PubMed  Google Scholar 

  • Portilla, D., Li, S., Nagothu, K. K., Megyesi, J., Kaissling, B., Schnackenberg, L., et al. (2006). Metabolomic study of cisplatin-induced nephrotoxicity. Kidney International, 69, 2194–2204.

    CAS  PubMed  Google Scholar 

  • Ramautar, R., Ratnayake, C. K., Somsen, G. W., & de Jong, G. J. (2009). Capillary electrophoresis-mass spectrometry using an in-line sol-gel concentrator for the determination of methionine enkephalin in cerebrospinal fluid. Talanta, 78, 638–642.

    CAS  PubMed  Google Scholar 

  • Reo, N. V. (2002). NMR-based metabolomics. Drug and Chemical Toxicology, 25, 375–382.

    CAS  PubMed  Google Scholar 

  • Robertson, D. G. (2005). Metabonomics in toxicology: A review. Toxicological Sciences, 85, 809–822.

    CAS  PubMed  Google Scholar 

  • Robertson, D. G., Reily, M. D., & Baker, J. D. (2005). Metabonomics in preclinical drug development. Expert Opinion on Drug Metabolism & Toxicology, 1, 363–376.

    CAS  Google Scholar 

  • Robertson, D. G., Reily, M. D., Sigler, R. E., Wells, D. F., Paterson, D. A., & Braden, T. K. (2000). Metabonomics: Evaluation of nuclear magnetic resonance (NMR) and pattern recognition technology for rapid in vivo screening of liver and kidney toxicants. Toxicological Sciences, 57, 326–337.

    CAS  PubMed  Google Scholar 

  • Roe, C. R., Millington, D. S., Maltby, D. A., & Kinnebrew, P. (1986). Recognition of medium-chain acyl-CoA dehydrogenase deficiency in asymptomatic siblings of children dying of sudden infant death or Reye-like syndromes. Journal of Pediatrics, 108, 13–18.

    CAS  PubMed  Google Scholar 

  • Schindhelm, R. K., Diamant, M., Dekker, J. M., Tushuizen, M. E., Teerlink, T., & Heine, R. J. (2006). Alanine aminotransferase as a marker of non-alcoholic fatty liver disease in relation to type 2 diabetes mellitus and cardiovascular disease. Diabetes/Metabolism Research and Reviews, 22, 437–443.

    CAS  PubMed  Google Scholar 

  • Schnackenberg, L. K. (2007). Global metabolic profiling and its role in systems biology to advance personalized medicine in the 21st century. Expert Review of Molecular Diagnostics, 7, 247–259.

    CAS  PubMed  Google Scholar 

  • Schnackenberg, L. K., Jones, R. C., Thyparambil, S., Taylor, J. T., Han, T., Tong, W., et al. (2006). An integrated study of acute effects of valproic acid in the liver using metabonomics, proteomics, and transcriptomics platforms. OMICS, 10, 1–14.

    CAS  PubMed  Google Scholar 

  • Schnackenberg, L. K., Sun, J., Espandiari, P., Holland, R. D., Hanig, J., & Beger, R. D. (2007). Metabonomics evaluations of age-related changes in the urinary compositions of male Sprague Dawley rats and effects of data normalization methods on statistical and quantitative analysis. BMC Bioinformatics, 8(7), S3.

    PubMed  Google Scholar 

  • Schultz, J. R., Tu, H., Luk, A., Repa, J. J., Medina, J. C., Li, L., et al. (2000). Role of LXRs in control of lipogenesis. Genes and Development, 14, 2831–2838.

    CAS  PubMed  Google Scholar 

  • Shi, C., Wu, C. Q., Cao, A. M., Sheng, H. Z., Yan, X. Z., & Liao, M. Y. (2007). NMR-spectroscopy-based metabonomic approach to the analysis of Bay41-4109, a novel anti-HBV compound, induced hepatotoxicity in rats. Toxicology Letters, 173, 161–167.

    CAS  PubMed  Google Scholar 

  • Smilde, A. K., van der Werf, M. J., Bijlsma, S., der Vat, B. J., & Jellema, R. H. (2005). Fusion of mass spectrometry-based metabolomics data. Analytical Chemistry, 77, 6729–6736.

    CAS  PubMed  Google Scholar 

  • Spagou, K., Tsoukali, H., Raikos, N., Gika, H., Wilson, I. D., & Theodoridis, G. (2010). Hydrophilic interaction chromatography coupled to MS for metabonomic/metabolomic studies. Journal of Separation Science, 33, 716–727.

    CAS  PubMed  Google Scholar 

  • Sun, J., Schnackenberg, L. K., Holland, R. D., Schmitt, T. C., Cantor, G. H., Dragan, Y. P., et al. (2008). Metabonomics evaluation of urine from rats given acute and chronic doses of acetaminophen using NMR and UPLC/MS. Journal of chromatography. B, Analytical Technologies in the Biomedical and Life Sciences, 871, 328–340.

    CAS  PubMed  Google Scholar 

  • Sun, J., Von Tungeln, L. S., Hines, W., & Beger, R. D. (2009). Identification of metabolite profiles of the catechol-O-methyl transferase inhibitor tolcapone in rat urine using LC/MS-based metabonomics analysis. Journal of chromatography. B, Analytical Technologies in the Biomedical and Life Sciences, 877, 2557–2565.

    CAS  PubMed  Google Scholar 

  • Sun, G., Yang, K., Zhao, Z. D., Guan, S. P., Han, X. L., & Gross, R. W. (2007). Shotgun metabolomics approach for the analysis of negatively charged water-soluble cellular metabolites from mouse heart tissue. Analytical Chemistry, 79, 6629–6640.

    CAS  PubMed  Google Scholar 

  • Tang, H., Wang, Y., Nicholson, J. K., & Lindon, J. C. (2004). Use of relaxation-edited one-dimensional and two dimensional nuclear magnetic resonance spectroscopy to improve detection of small metabolites in blood plasma. Analytical Biochemistry, 325, 260–272.

    CAS  PubMed  Google Scholar 

  • Theodoridis, G., Gika, H. G., & Wilson, I. D. (2008). LC-MS-based methodology for global metabolite profiling in metabonomics/metabolomics. TrAC Trends in Analytical Chemistry, 27, 251–260.

    CAS  Google Scholar 

  • Ulven, S. M., Dalen, K. T., Gustafsson, J. A., & Nebb, H. I. (2005). LXR is crucial in lipid metabolism. Prostaglandins Leukotrienes and Essential Fatty Acids, 73, 59–63.

    CAS  Google Scholar 

  • van der Werf, M. J., Overkamp, K. M., Muilwijk, B., Coulier, L., & Hankemeier, T. (2007). Microbial metabolomics: Toward a platform with full metabolome coverage. Analytical Biochemistry, 370, 17–25.

    PubMed  Google Scholar 

  • Wang, J., Einarsson, C., Murphy, C., Parini, P., Bjorkhem, I., Gafvels, M., et al. (2006a). Studies on LXR- and FXR-mediated effects on cholesterol homeostasis in normal and cholic acid-depleted mice. Journal of Lipid Research, 47, 421–430.

    CAS  PubMed  Google Scholar 

  • Wang, N., Ranalletta, M., Matsuura, F., Peng, F., & Tall, A. R. (2006b). LXR-induced redistribution of ABCG1 to plasma membrane in macrophages enhances cholesterol mass efflux to HDL. Arteriosclerosis, Thrombosis, and Vascular Biology, 26, 1310–1316.

    CAS  PubMed  Google Scholar 

  • Wang, J., Reijmers, T., Chen, L., Van Der Heijden, R., Wang, M., Peng, S., et al. (2009). Systems toxicology study of doxorubicin on rats using ultra performance liquid chromatography coupled with mass spectrometry based metabolomics. Metabolomics, 5, 407–418.

    CAS  PubMed  Google Scholar 

  • Watson, D. G. (1994). TITLE. In P. Baugh (Ed.), Gas chromatography: A practical approach (pp. 133–169). Oxford: IRL Press.

    Google Scholar 

  • Williams, R. E., Lenz, E. M., Evans, J. A., Wilson, I. D., Granger, J. H., Plumb, R. S., et al. (2005a). A combined (1)H NMR and HPLC-MS-based metabonomic study of urine from obese (fa/fa) Zucker and normal Wistar-derived rats. Journal of Pharmaceutical and Biomedical Analysis, 38, 465–471.

    CAS  PubMed  Google Scholar 

  • Williams, R. E., Lenz, E. M., Lowden, J. S., Rantalainen, M., & Wilson, I. D. (2005b). The metabonomics of aging and development in the rat: An investigation into the effect of age on the profile of endogenous metabolites in the urine of male rats using 1H NMR and HPLC-TOF MS. Molecular bioSystems, 1, 166–175.

    CAS  PubMed  Google Scholar 

  • Wilson, I. D., Plumb, R., Granger, J., Major, H., Williams, R., & Lenz, E. M. (2005). HPLC-MS-based methods for the study of metabonomics. Journal of chromatography. B, Analytical Technologies in the Biomedical and Life Sciences, 817, 67–76.

    CAS  PubMed  Google Scholar 

  • Wu, H., Southam, A. D., Hines, A., & Viant, M. R. (2008). High-throughput tissue extraction protocol for NMR- and MS-based metabolomics. Analytical Biochemistry, 372, 204–212.

    CAS  PubMed  Google Scholar 

  • Yang, J., Song, S. L., Castro-Perez, J., Plumb, R. S., & Xu, G. W. (2005). Metabonomics and its applications. Sheng Wu Gong Cheng Xue Bao, 21, 1–5.

    PubMed  Google Scholar 

  • Zammit, V. A., Ramsay, R. R., Bonomini, M., & Arduini, A. (2009). Carntine, mitochondrial function and therapy. Advanced Drug Delivery Reviews, 61, 1353–1362.

    CAS  PubMed  Google Scholar 

  • Zhang, X., Rauch, A., Lee, H., Xiao, H., Rainer, G., & Logothetis, N. K. (2007). Capillary hydrophilic interaction chromatography/mass spectrometry for simultaneous determination of multiple neurotransmitters in primate cerebral cortex. Rapid Communications in Mass Spectrometry, 21, 3621–3628.

    CAS  PubMed  Google Scholar 

  • Zhang, Y., Repa, J. J., Inoue, Y., Hayhurst, G. P., Gonzalez, F. J., & Mangelsdorf, D. J. (2004). Identification of a liver-specific uridine phosphorylase that is regulated by multiple lipid-sensing nuclear receptors. Molecular Endocrinology, 18, 851–862.

    CAS  PubMed  Google Scholar 

  • Zheng, L., T’Kind, R., Decuypere, S., von Freyend, S. J., Coombs, G. H., & Watson, D. G. (2010). Profiling of lipids in Leishmania donovani using hydrophilic interaction chromatography in combination with Fourier transform mass spectrometry. Rapid Communications in Mass Spectrometry, 24, 2074–2082.

    CAS  PubMed  Google Scholar 

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Acknowledgments

The authors wish to thank the BBSRC and Schering-Plough Research Organisation for funding for PhD CASE studentship for L.M.

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Authors and Affiliations

  1. Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 27 Taylor Street, Glasgow, G4 0NR, UK

    Lynsey MacIntyre, Liang Zheng & David G. Watson

  2. Schering-Plough (Part of the MSD Organisation), Research Laboratories, Newhouse, Motherwell, ML1 5SH, UK

    Paul Scullion

  3. Department of Pure and Applied Chemistry, University of Strathclyde, Thomas Graham Building, 295 Cathedral Street, Glasgow, G1 1XL, UK

    Pat Keating

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  1. Lynsey MacIntyre
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  2. Liang Zheng
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  3. Paul Scullion
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  4. Pat Keating
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  5. David G. Watson
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Correspondence to David G. Watson.

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MacIntyre, L., Zheng, L., Scullion, P. et al. Metabolomic profiling of biomarkers of liver X receptor-induced toxicity in mouse liver tissue. Metabolomics 7, 54–70 (2011). https://doi.org/10.1007/s11306-010-0235-6

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  • DOI: https://doi.org/10.1007/s11306-010-0235-6

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