Applications of NMR-Based Metabonomic Approaches in the Assessment of Drug Toxicity

Abstract

Abstract:

Metabonomics studies the variations of levels of endogenous metabolites in response to physiological rhythms and external stimuli, providing molecular mechanistic explanations to the effects of pathology, toxins or specific environmental conditions. It has become an important tool in systems biology. With metabonomic approaches, mass spectrometry or nuclear magnetic resonance (NMR) spectroscopy data acquired from biological samples are analyzed with pattern recognition techniques. These approaches have been successfully applied in many research areas, including biomedicine and drug toxicology. In this review, we focused on experimental design, assessment of NMR spectroscopy, pattern recognition techniques and applications of NMR-based metabonomic approaches in studying drug toxicology.

Key words: nuclear magnetic resonance, metabonomics, pattern recognition, drug toxicology

CLC Number:

O482.53

HAO Xiu-Ju, WANG Yu-Lan. Applications of NMR-Based Metabonomic Approaches in the Assessment of Drug Toxicity[J]. Chinese Journal of Magnetic Resonance, 2011, 28(1): 1-17.

References

[1] Tang H R，Wang Y L. Metabonomics：a revolution in progress[J]. Prog Biochem Biophys，2006，33(5): 401-407.

[2] Nicholson J K，Lindon J C，Holmes E. ‘Metabonomics’: understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data[J]. Xenobiotica，1999，29（11）: 1 181-1 189.

[3] Oliver S G. From DNA sequence to biological function:the new voyage of the Beagle[J]. Biochem Soc Trans，1996，24（1）: 291-292.

[4] Oliver S G. Functional genomics: lessons from yeast[J]. Phil Trans R Soc Lond B，2002，357（1 417）: 17-23.

[5] Tweeddale H， Notley-McRobb L，Ferenci T. Effect of slow growth on metabolism of Escherichia coli，as revealed by global metabolite pool (‘metabolome’) analysis[J]. J Bacteriol，1998，180（19）: 5 109-5 116.

[6] Griffin J L. Metabonomics: NMR spectroscopy and pattern recognition analysis of body fluids and tissues for characterisation of xenobiotic toxicity and disease diagnosis[J]. Curr Opin Chem Biol，2003，7(5): 648-654.

[7] Lindon J C，Nicholson J K. Analytical technologies for metabonomics and metabolomics，and multi-omic information recovery[J]. TrAC Trend Anal Chem，2008，27(3): 194-204.

[8] Azmi J，Griffin J L，Shore R F，et al. Chemometric analysis of biofluids following toxicant induced hepatotoxicity: a metabonomic approach to distinguish the effects of 1-naphthylisothiocyanate from its products[J]. Xenobiotica，2005，35(8): 839-852.

[9] Holmes E，Antti H. Chemometric contributions to the evolution of metabonomics: mathematical solutions to characterising and interpreting complex biological NMR spectra[J]. Analyst，2002，127(12): 1 549-1 557.

[10] Wang Y L，Lawler D，Larson B，et al. Metabonomic investigations of aging and caloric restriction in a life-long dog study[J]. J Proteome Res，2007，6(5): 1 846-1 854.

[11] Holmes E，Loo R L，Stamler J，et al. Human metabolic phenotype diversity and its association with diet and blood pressure[J]. Nature，2008，453(7 193): 396-400.

[12] Wang Y L，Holmes E，Tang H R，et al. Experimental metabonomic model of dietary variation and stress interactions[J]. J Proteome Res，2006，5(7): 1 535-1 542.

[13] Wang Y L，Tang H R，Nicholson J K，et al. A metabonomic strategy for the detection of the metabolic effects of chamomile (Matricaria recutita L.) ingestion[J]. J Agr Food Chem，2005，53(2): 191-196.

[14] Wang Y L，Tang H R，Nicholson J K，et al. Metabolomic strategy for the classification and quality control of phytomedicine: A case study of chamomile flower (Matricaria recutita L.)[J]. Planta Med，2004，70(3): 250-255.

[15] Wang Y，Holmes E，Comelli E M，et al. Topographical variation in metabolic signatures of human gastrointestinal biopsies revealed by high-resolution magic-angle spinning ¹H NMR spectroscopy[J]. J Proteome Res，2007，6(10): 3 944-3 951.

[16] Wang Y，Tang H，Holmes E，et al. Biochemical characterization of rat intestine development using high-resolution magic-anglespinning ¹H NMR spectroscopy and multivariate data analysis[J]. J Proteome Res，2005，4(4): 1 324-1 329.

[17] Saric J，Wang Y，Li J，et al. Species variation in the fecal metabolome gives insight into differential gastrointestinal function[J]. J Proteome Res，2008，7(1): 352-360.

[18] Holmes E，Wilson I D，Nicholson J K. Metabolic phenotyping in health and disease[J]. Cell，2008，134(5): 714-717.

[19] Wang Y L，Utzinger J，Saric J，et al. Global metabolic responses of mice to Trypanosoma brucei brucei infection[J]. P Natl Acad Sci USA，2008，105(16): 6 127-6 132.

[20] Wang Y L，Holmes E，Nicholson J K，et al. Metabonomic investigations in mice infected with Schistosoma mansoni: an approach for biomarker identification[J]. P Natl Acad Sci USA，2004，101(34): 12 676-12 681.

[21] Wang Y L，Utzinger J，Xiao S H， et al. System level metabolic effects of a Schistosoma japonicum infection in the Syrian hamster[J]. Mol Biochem Parasit，2006，146(1): 1-9.

[22] Lindon J C，Holmes E，Nicholson J K. Toxicological applications of magnetic resonance[J]. Prog Nucl Mag Res Sp，2004，45(1-2): 109-143.

[23] Ebbels T，Keun H，Beckonert O，et al. Toxicity classification from metabonomic data using a density superposition approach: ‘CLOUDS’[J]. Anal Chim Acta，2003，490(1-2): 109-122.

[24] Yap I K S，Clayton T A，Tang H，et al. An integrated metabonomic approach to describe temporal metabolic disregulation induced in the rat by the model hepatotoxin allyl formate[J]. J Proteome Res，2006，5(10): 2 675-2 684.

[25] Beckwith-Hall B M，Nicholson J K，Nicholls A W，et al. Nuclear magnetic resonance spectroscopic and principal components analysis investigations into biochemical effects of three model hepatotoxins[J]. Chem Res Toxicol，1998，11(4): 260-272.

[26] Ebbels T M D，Holmes E，Lindon J C，et al. Evaluation of metabolic variation in normal rat strains from a statistical analysis of ¹H NMR spectra of urine[J]. J Pharm Biomed Anal，2004，36(4): 823-833.

[27] Stanley E G，Bailey N J C，Bollard M E，et al. Sexual dimorphism in urinary metabolite profiles of Han Wistar rats revealed by nuclear-magnetic-resonance-based metabonomics[J]. Anal Biochem，2005，343(2): 195-202.

[28] Saude E J，Adamko D，Rowe B H，et al. Variation of metabolites in normal human urine[J]. Metabolomics，2007，3(2): 439-451.

[29] Wang Y， Xiao S H， Xue J，et al. Systems metabolic effects of a Necator americanus infection in Syrian hamster[J]. J Proteome Res，2009，8(12): 5 442-5 450.

[30] Gavaghan C L，Holmes E，Lenz E，et al. An NMRbased metabonomic approach to investigate the biochemical consequences of genetic strain differences: application to the C57BL10J and Alpk : ApfCD mouse[J]. Febs Lett，2000，484(3): 169-174.

[31] Gipson G T，Tatsuoka K S，Ball R J，et al. Multi-platform investigation of the metabolome in a leptin receptor defective murine model of type 2 diabetes[J]. Mol Biosyst，2008，4(10): 1 015-1 023.

[32] Leo G C，Darrow A L.NMR-based metabolomics of urine for the atherosclerotic mouse model using apolipoprotein-E deficient mice\
[J\].Magn Reson Chem，2009，47(Sp.1): S20-S25.

[33] Bollard M E，Keun H C，Beckonert O，et al.Comparative metabonomics of differential hydrazine toxicity in the rat and mouse[J]. Toxicol Appl Pharm，2005 ，204(2): 135-151.

[34] Holmes E，Bonner F W，Nicholson J K.Comparative biochemical effects of low doses of mercury II chloride in the F344 rat and the multimammate mouse (Mastomys natalensis) [J]. Comp Biochem Phys C，1996，114(1): 7-15.

[35] Holmes E，Bonner F W，Nicholson J K. ¹H NMR spectroscopic and histopathological studies on propyleneimine-induced renal papillary necrosis in the rat and the multimammate desert mouse (Mastomys natalensis)[J]. Comp Biochem Phys C，1997，116(2): 125-134.

[36] Jones A R. Some observations on the urinary excretion of glycine conjugates by laboratory animals[J]. Xenobiotica，1982，12(6): 387-395.

[37] Costa C，Deantoni A，Baccichetti F，et al. Strain differences in the tryptophan metabolite excretion and enzyme-activities along the kynurenine pathway in rats[J]. Ital J Biochem ，1982，31(6): 412-418.

[38] Costa C，Deantoni A，Baccichetti F，et al. Metabolites and enzyme-activities involved in tryptophan-metabolism in 2 different strains of mouse[J]. Ital J Biochem ，1984，33(5): 319-324.

[39] Holmes E，Nicholls AW，Lindon J C，et al. Chemometric models for toxicity classification based on NMR spectra of biofluids[J]. Chem Res Toxicol ，2000，13(6): 471-478.

[40] Bell J D，Sadler P J，Morris V C，et al. Effect of aging and diet on proton NMR-spectra of rat urine[J]. Magn Reson Med ，1991, 17(2): 414-422.

[41] Bollard M E，Holmes E，Lindon J C，et al. Investigations into biochemical changes due to diurnal variation and estrus cycle in female rats using high-resolution ¹H NMR spectroscopy of urine and pattern recognition[J]. Anal Biochem，2001，295(2): 194-202.

[42] Zuppi C，Messana I，Forni F，et al. ¹H NMR spectra of normal urines: Reference ranges of the major metabolites[J]. Clin Chim Acta，1997，265(1): 85-97.

[43] Bollard M E，Stanley E G，Lindon J C，et al. NMR-based metabonomic approaches for evaluating physiological influences on biofluid composition[J]. NMR Biomed，2005，18(3): 143-162.

[44] Nicholls A W，Mortishire-Smith R J，Nicholson J K. NMR spectroscopic-based metabonomic studies of urinary metabolite variation in acclimatizing germ-free rats[J]. Chem Res Toxicol，2003，16(11): 1 395-1 404.

[45] Xiao C N，Hao F H，Qin X R. et al. An optimized buffer system for NMR-based urinary metabonomics with effective pH control， chemical shift consistency and dilution minimization[J]. Analyst，2009，134(5): 916-925.

[46] Beckonert O，Keun H C，Ebbels T M D，et al. Metabolic profiling，metabolomic and metabonomic procedures for NMR spectroscopy of urine，plasma，serum and tissue extracts[J]. Nat Protoc，2007，2(11): 2 692-2 703.

[47] Wang Y L，Bollard M E，Keun H，et al. Spectral editing and pattern recognition methods applied to high-resolution magic-angle spinning ¹H nuclear magnetic resonance spectroscopy of liver tissues[J]. Anal Biochem，2003，323(1): 26-32.

[48] Smith L M，Maher A D，Cloarec O，et al. Statistical correlation and projection methods for improved information recovery from diffusion-edited NMR spectra of biological samples[J]. Anal Chem，2007，79(15): 5 682-5 689.

[49] Wang Y L，Cloarec O，Tang H R，et al. Magic angle spinning NMR and ¹H-³¹P heteronuclear statistical total correlation spectroscopy of intact human gut biopsies[J]. Anal Chem，2008，80(4): 1 058-1 066.

[50] Wold S，Esbensen K，Geladi P. Principal component analysis[J]. Chemometr Intell Lab，1987，2(1-3): 37-52.

[51] Jackson J E. A user’s guide to principal components (Wiley Ser Probab Stat)[M]. New York: Wiley-Interscience, 2003. xvii，569.

[52] Jackson J E，Mudholkar G S. Control procedures for residuals associated with principal component analysis[J]. Technometrics， 1979，21(3): 341-349.

[53] Beckonert O E, Bollard M，Ebbels T M D，et al. NMR-based metabonomic toxicity classification: hierarchical cluster analysis and knearest-neighbour approaches[J]. Anal Chim Acta，2003，490(1-2): 3-15.

[54] Haaland D M，Thomas E V. Partial least-squares methods for spectral analyses. 1. Relation to other quantitative calibration methods and the extraction of qualitative information[J]. Anal Chem，1988，60(11): 1 193-1 202.

[55] Haaland D M，Thomas E V. Partial least-squares methods for spectral analyses. 2. Application to simulated and glass spectral data[J]. Anal Chem，1988，60(11): 1 202-1 208.

[56] Hoskuldsson A. Variable and subset selection in PLS regression[J]. Chemometr Intell Lab，2001，55(1-2): 23-38.

[57] Wold S，Ruhe A，Wold H，et al. The collinearity problem in linear regression. The partial least squares approach to generalized inverses[J]. SIAM J Sci Stat Comput，1984，5(3): 735-743.

[58] Jiang H W, Xia J I. Partial least square and its application[J]. J Fourth Mil Med Univ，2003，24(3): 280-283.

[59] Cloarec O，Dumas M E，Trygg J，et al. Evaluation of the orthogonal projection on latent structure model limitations caused by chemical shift variability and improved visualization of biomarker changes in ¹H NMR spectroscopic metabonomic studies[J]. Anal Chem， 2005，77(2): 517-526.

[60] Trygg J，Wold S. Orthogonal projections to latent structures (O-PLS)[J]. J Chemometr，2002，16(3): 119-128.

[61] Bylesjo M，Rantalainen M，Cloarec O，et al. OPLS discriminant analysis: combining the strengths of PLS-DA and SIMCA classification[J]. J Chemometr，2007，20(8-10): 341-351.

[62] Trygg J. O2-PLS for qualitative and quantitative analysis in multivariate calibration[J]. J Chemometr，2002，16(6): 283-293.

[63] Trygg J，Wold S. O2-PLS， a two-block (X-Y) latent variable regression (LVR) method with an integral OSC filter[J]. J Chemometr， 2003，17（1）：53-64

[64] Rantalainen M，Cloarec O，Beckonert O，et al. Statistically integrated metabonomic-proteomic studies on a human prostate cancer xenograft model in mice[J]. J Proteome Res，2006，5(10): 2 642-2 655.

[65] Lindgren F，Hansen B，Karcher W， et al. Model validation by permutation tests: applications to variable selection[J]. J Chemometr，1996，10(5-6): 521-532.

[66] Umetrics A B. User guide to SIMCA-P+12[M]. Kinnelon: Umetrics Inc，2008. 

[67] Johnson C H，Athersuch T J，Wilson I D，et al. Kinetic and J-resolved statistical total correlation NMR spectroscopy approaches to structural information recovery in complex reacting mixtures: application to acyl glucuronide intramolecular transacylation reactions[J]. Anal Chem，2008，80(13): 4 886-4 895.

[68] Nicholson J K，Kendall M D，Osborn D. Cadmium and mercury nephrotoxicity[J]. Nature，1983，304(5 927): 633-635.

[69] Griffin J L，Walker L A，Shore R F. Metabolic profiling of chronic cadmium exposure in the rat[J]. Chem Res Toxicol，2001，14(10): 1 428-1 434.

[70] Griffin J，Walker L，Shore R，et al. High-solution magic angle spinning ¹H NMR spectroscopy studies on the renal biochemistry in the bank vole (Clethrionomys glareolus) and the efects of arsenic (As³⁺)toxicity[J]. Xenobiotica，2001，31(6): 377-385.

[71] Griffin J L，Kenn H，Richter C，et al. Compartmentation of metabolism probed by [2-¹³C]alanine: improved ¹³C NMR sensitivity using a CryoProbe detects evidence of a glial metabolon[J]. Neurochem Int，2003，42(1): 93-99.

[72] Griffin J L，Walker L A，Garrod S，et al. NMR spectroscopy based metabonomic studies on the comparative biochemistry of the kidney and urine of the bank vole (Clethrionomys glareolus)，wood mouse (Apodemus sylvaacus)，white toothed shrew (Crocidura suaveolena) and the laboratory rat[J]. Comp Biochem Phys B，2000，127(3): 357-367.

[73] Wang Y L，Bollard M E，Nicholson J K，et al. Exploration of the direct metabolic effects of mercury II chloride on the kidney of Sprague-Dawley rats using high-resolution magic angle spinning ¹H NMR spectroscopy of intact tissue and pattern recognition[J]. J Pharmaceut Biomed，2006，40(2): 375-381.

[74] Holmes E，Boner F W，Sweatman B C，et al. Nuclear-magnetic-resonance spectroscopy and pattern-recognition analysis of the biochemical processes associated witll the progression of and recovery from nephrotoxic lesions in the rat induced by mercury(II) chloride and 2-bromoethanamine[J]. Mol Pharmacol，1992，42(5): 922-930.

[75] Feng J，Li X，Pei F，et al. ¹H NMR analysis for metabolites in serum and urine from rats administrated chronically with La(NO₃)₃[J]. Anal Biochem，2002，301(1): 1-7.

[76] Wu H F，Zhang X Y，Li X J，et al. Acute biochemical efects of La(NO₃)₃ on liver and kindey tissues by magic-angle spining ¹H nuclear magnetic resonance spectroscopy and patern recognition[J]. Anal Biochem，2005，339(2): 242-248.

[77] Wu H F，Zhang X Y，Li X J，et al. Studies on the acute biochemical effects of La(NO₃)₃using ¹H NMR spectroscopy of urine combined with pattern recognition[J]. J Inorg Biochem，2005，99(2): 644-650.

[78] Wu H F，Zhang X Y，Liao P，et al. NMR spectroscopic-based metabonomic investigation on the acute biochemical effects induced by Ce(NO₃)₃ in rats[J]. J Inorg Biochem，2005，99(11): 2 151-2 160.

[79] Coen M，Lenz E M，Nicholson J K，et al. An integrated metabonomic investigation of acetaminophen toxicity in the mouse using NMR spectroscopy[J]. Chem Res Toxicol，2003，16(3): 295-303.

[80] Coen M，Hong Y S，Clayton T A，et al. The mechanism of galactosamine toxicity revisited; A metabonomic study[J]. J Proteome Res，2007，6(7): 2 711-2 719.

[81] Ding L，Hao F，Shi Z，et al. Systems biological responses to chronic perfluorododecanoic acid exposure by integrated metabonomic and transcriptomic studies[J]. J Proteome Res，2009，8(6): 2 882-2 891.

[82] Nicholson J K，Connelly J，Lindon J C，et al. Metabonomics: a platform for studying drug toxicity and gene function[J]. Nat Rev Drug Discov，2002，1(2): 153-161.

[83] Ebbels T M D，Keun H C，Beckonert O P，et al. Prediction and classification of drug toxicity using probabilistic modeling of temporal metabolic data: the consortium on metabonomic toxicology screening approach[J]. J Proteome Res，2007，6(11): 4 407-4 422.

[84] Lindon J C，Nicholson J K，Holmes E，et al. Contemporary issues in toxicology the role of metabonomics in toxicology and its evaluation by the COMET project[J].Toxicol Appl Pharmacol，2003，187(3): 137-146.

[85] Lindon J C，Keun H C，Ebbels T M D，et al. The Consortium for Metabonomic Toxicology (COMET): aims，activities and achievements[J]. Pharmacogenomics，2005，6 (7): 691-699.

[86] Nicholson J K，Lindon J C. Systems biology -Metabonomics[J] .Nature，2008，455(7 216): 1 054-1 056.

[87] Nicholson J K，Wilson I D. Understanding ‘global’systems biology: metabonomics and the continuum of metabolism[J]. Nat Rev Drug Discov，2003，2(8): 668-676.

[88] Clayton T A L，John C. Cloarec O，et al. Pharmaco-metabonomic phenotyping and personalized drug treatment[J]. Nature，2006， 440(7 087): 1 073-1 077.

[89] Clayton T A L，Baker D，Lindon J C，et al. Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism[J]. P Natl Acad Sci USA，2009 ，106(34): 14 728-14 733.

[90] Hao Bo-lin(郝柏林). Starting with parabolas——An introduction to chaotic dynamics(从抛物线谈起——混沌动力学引论)[M]. Shanghai(上海)：Shanghai Scientific and Technical Education Publishing House(上海科技教育出版社)，1993.

[91] Friedrich Cramer, translated by Ke zhi-yang and Wu Tong(克拉默著，柯志阳、吴彤泽译，混沌与秩序). Chaos and order: Complex structure of biological systems(生物系统的复杂结构)[M]. Shanghai(上海)：Shanghai Scientific and Technical Education Publishing House(上海科技教育出版社)，2000.

[92] Jia W，Li H，Zhao L，et al. Gut microbiota: a potential new territory for drug targeting[J]. Nat Rev Drug Discov，2008，7(2): 123-129.