Metabonomics Techniques and Applications to Pharmaceutical Research & Development

In this review, the background to the approach known as metabonomics is provided, giving a brief historical perspective and summarizing the analytical and statistical techniques used. Some of the major applications of metabonomics relevant to pharmaceutical Research & Development are then reviewed including the study of various influences on metabolism, such as diet, lifestyle, and other environmental factors. The applications of metabonomics in drug safety studies are explained with special reference to the aims and achievements of the Consortium for Metabonomic Toxicology. Next, the role that metabonomics might have in disease diagnosis and therapy monitoring is provided with some examples, and the concept of pharmacometabonomics as a way of predicting an individual's response to treatment is highlighted. Some discussion is given on the strengths and weaknesses, opportunities of, and threats to metabonomics.

[1]  J. Nielsen,et al.  Global metabolite analysis of yeast: evaluation of sample preparation methods , 2005, Yeast.

[2]  U. Engelke,et al.  Proton nuclear magnetic resonance spectroscopy of body fluids in the field of inborn errors of metabolism , 2003, Annals of clinical biochemistry.

[3]  Jeremy K Nicholson,et al.  An integrated reverse functional genomic and metabolic approach to understanding orotic acid-induced fatty liver. , 2004, Physiological genomics.

[4]  J. Lindon,et al.  Metabonomics: a platform for studying drug toxicity and gene function , 2002, Nature Reviews Drug Discovery.

[5]  Elaine Holmes,et al.  The challenges of modeling mammalian biocomplexity , 2004, Nature Biotechnology.

[6]  D. Gauguier,et al.  Statistical total correlation spectroscopy: an exploratory approach for latent biomarker identification from metabolic 1H NMR data sets. , 2005, Analytical chemistry.

[7]  R. Kauppinen,et al.  Metabolite Changes in BT4C Rat Gliomas Undergoing Ganciclovir-Thymidine Kinase Gene Therapy-induced Programmed Cell Death as Studied by 1H NMR Spectroscopy in Vivo, ex Vivo, and in Vitro* , 2003, Journal of Biological Chemistry.

[8]  J C Lindon,et al.  Directly coupled HPLC-NMR and HPLC-NMR-MS in pharmaceutical research and development. , 2000, Journal of chromatography. B, Biomedical sciences and applications.

[9]  O. Fiehn.  Metabolomics – the link between genotypes and phenotypes , 2004, Plant Molecular Biology.

[10]  Jeremy K Nicholson,et al.  NMR spectroscopic-based metabonomic studies of urinary metabolite variation in acclimatizing germ-free rats. , 2003, Chemical research in toxicology.

[11]  J. Lindon,et al.  NMR‐based metabonomic approaches for evaluating physiological influences on biofluid composition , 2005, NMR in biomedicine.

[12]  Franklyn A. Howe,et al.  Comparison of in vivo1H MRS of human brain tumours with1H HR-MAS spectroscopy of intact biopsy samples in vitro , 1999, Magnetic Resonance Materials in Physics, Biology and Medicine.

[13]  R. Gonzalez,et al.  Correlation of high-resolution magic angle spinning proton magnetic resonance spectroscopy with histopathology of intact human brain tumor specimens. , 1998, Cancer research.

[14]  Muireann Coen,et al.  Proton nuclear magnetic resonance-based metabonomics for rapid diagnosis of meningitis and ventriculitis. , 2005, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[15]  S. Watkins,et al.  Focused metabolomic profiling in the drug development process: advances from lipid profiling. , 2005, Current opinion in chemical biology.

[16]  G. W. Hatfield,et al.  DNA microarrays and gene expression , 2002 .

[17]  Elaine Holmes,et al.  The Consortium for Metabonomic Toxicology (COMET): aims, activities and achievements. , 2005, Pharmacogenomics.

[18]  E Holmes,et al.  Metabonomic characterization of genetic variations in toxicological and metabolic responses using probabilistic neural networks. , 2001, Chemical research in toxicology.

[19]  Henrik Antti,et al.  Contemporary issues in toxicology the role of metabonomics in toxicology and its evaluation by the COMET project. , 2003, Toxicology and applied pharmacology.

[20]  J. Griffin,et al.  Cryogenic probe 13C NMR spectroscopy of urine for metabonomic studies. , 2002, Analytical chemistry.

[21]  John C. Lindon,et al.  Metabolomics Standards Workshop and the development of international standards for reporting metabolomics experimental results , 2006, Briefings Bioinform..

[22]  E Holmes,et al.  NMR and pattern recognition studies on the time-related metabolic effects of alpha-naphthylisothiocyanate on liver, urine, and plasma in the rat: an integrative metabonomic approach. , 2001, Chemical research in toxicology.

[23]  Alan Hutson,et al.  Detection of epithelial ovarian cancer using 1H‐NMR‐based metabonomics , 2005, International journal of cancer.

[24]  Paul H. Gamache,et al.  Metabolomic applications of electrochemistry/Mass spectrometry , 2004, Journal of the American Society for Mass Spectrometry.

[25]  Douglas B. Kell,et al.  Functional Genomics Via Metabolic Footprinting: Monitoring Metabolite Secretion by Escherichia Coli Tryptophan Metabolism Mutants Using FT–IR and Direct Injection Electrospray Mass Spectrometry , 2003, Comparative and functional genomics.

[26]  T. Ebbels,et al.  Geometric trajectory analysis of metabolic responses to toxicity can define treatment specific profiles. , 2004, Chemical research in toxicology.

[27]  E Holmes,et al.  High‐resolution magic angle spinning 1H NMR spectroscopic studies on intact rat renal cortex and medulla , 1999, Magnetic resonance in medicine.

[28]  J. Lindon,et al.  'Metabonomics': understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. , 1999, Xenobiotica; the fate of foreign compounds in biological systems.

[29]  Douglas B. Kell,et al.  Metabolomics and Machine Learning: Explanatory Analysis of Complex Metabolome Data Using Genetic Programming to Produce Simple, Robust Rules , 2004, Molecular Biology Reports.

[30]  Nigel W. Hardy,et al.  A proposed framework for the description of plant metabolomics experiments and their results , 2004, Nature Biotechnology.

[31]  J C Lindon,et al.  Application of pattern recognition methods to the analysis and classification of toxicological data derived from proton nuclear magnetic resonance spectroscopy of urine. , 1991, Molecular pharmacology.

[32]  M. Tomita,et al.  Quantitative metabolome analysis using capillary electrophoresis mass spectrometry. , 2003, Journal of proteome research.

[33]  T. Ebbels,et al.  Analytical reproducibility in (1)H NMR-based metabonomic urinalysis. , 2002, Chemical research in toxicology.

[34]  T. Claridge.  High-Resolution NMR Techniques in Organic Chemistry , 1999 .

[35]  John C. Lindon,et al.  NMR Spectroscopy of Biofluids , 1999 .

[36]  J C Lindon,et al.  Biochemical classification of kidney carcinoma biopsy samples using magic-angle-spinning 1H nuclear magnetic resonance spectroscopy. , 1998, Journal of pharmaceutical and biomedical analysis.

[37]  Robert S Plumb,et al.  Statistical heterospectroscopy, an approach to the integrated analysis of NMR and UPLC-MS data sets: application in metabonomic toxicology studies. , 2006, Analytical chemistry.

[38]  Manuel Mayr,et al.  Proteomic and Metabolomic Analyses of Atherosclerotic Vessels From Apolipoprotein E-Deficient Mice Reveal Alterations in Inflammation, Oxidative Stress, and Energy Metabolism , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[39]  P. Carroll,et al.  Proton HR‐MAS spectroscopy and quantitative pathologic analysis of MRI/3D‐MRSI‐targeted postsurgical prostate tissues , 2003, Magnetic resonance in medicine.

[40]  John C. Lindon,et al.  Pattern recognition methods and applications in biomedical magnetic resonance , 2001 .

[41]  John C. Lindon,et al.  Metabonomics: metabolic processes studied by NMR spectroscopy of biofluids , 2000 .

[42]  Steven Mennerick,et al.  An integrated functional genomics and metabolomics approach for defining poor prognosis in human neuroendocrine cancers. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[43]  John C Lindon,et al.  An integrated metabonomic investigation of acetaminophen toxicity in the mouse using NMR spectroscopy. , 2003, Chemical research in toxicology.

[44]  Nigel W. Hardy,et al.  Summary recommendations for standardization and reporting of metabolic analyses , 2005, Nature Biotechnology.

[45]  Julian L Griffin,et al.  Metabolites from cerebrospinal fluid in aneurysmal subarachnoid haemorrhage correlate with vasospasm and clinical outcome: a pattern‐recognition 1H NMR study , 2005, NMR in biomedicine.

[46]  John C. Lindon,et al.  Toxicological applications of magnetic resonance , 2004 .

[47]  S. Wold,et al.  Orthogonal projections to latent structures (O‐PLS) , 2002 .

[48]  I. Wilson,et al.  High resolution "ultra performance" liquid chromatography coupled to oa-TOF mass spectrometry as a tool for differential metabolic pathway profiling in functional genomic studies. , 2005, Journal of proteome research.

[49]  Kieran Clarke,et al.  A Functional Analysis of Mouse Models of Cardiac Disease through Metabolic Profiling* , 2005, Journal of Biological Chemistry.

[50]  J C Lindon,et al.  Pattern recognition analysis of high resolution 1H NMR spectra of urine. A nonlinear mapping approach to the classification of toxicological data , 1990, NMR in biomedicine.

[51]  J. Griffin,et al.  Metabolic profiling of the effects of D-galactosamine in liver spheroids using (1)H NMR and MAS-NMR spectroscopy. , 2002, Chemical research in toxicology.

[52]  Henrik Antti,et al.  Comparative metabonomics of differential hydrazine toxicity in the rat and mouse. , 2005, Toxicology and applied pharmacology.

[53]  John C Lindon,et al.  Integrated application of transcriptomics and metabonomics yields new insight into the toxicity due to paracetamol in the mouse. , 2004, Journal of pharmaceutical and biomedical analysis.

[54]  Henrik Antti,et al.  Rapid and noninvasive diagnosis of the presence and severity of coronary heart disease using 1H-NMR-based metabonomics , 2003, Nature Medicine.

[55]  J. Lindon,et al.  Pharmaco-metabonomic phenotyping and personalized drug treatment , 2006, Nature.

[56]  M. Spraul,et al.  750 MHz 1H and 1H-13C NMR spectroscopy of human blood plasma. , 1995, Analytical chemistry.

[57]  M. Tanner,et al.  Metabonomic investigations in mice infected with Schistosoma mansoni: an approach for biomarker identification. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[58]  Donald G Robertson,et al.  Metabonomic identification of two distinct phenotypes in Sprague-Dawley (Crl:CD(SD)) rats. , 2005, Toxicological sciences : an official journal of the Society of Toxicology.

[59]  Timothy M. D. Ebbels,et al.  Toxicity classification from metabonomic data using a density superposition approach: ‘CLOUDS’ , 2003 .

[60]  F. Westwood,et al.  Metabonomics with 1H-NMR spectroscopy and liquid chromatography-mass spectrometry applied to the investigation of metabolic changes caused by gentamicin-induced nephrotoxicity in the rat , 2005, Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals.

[61]  J C Lindon,et al.  High-resolution diffusion and relaxation edited one- and two-dimensional 1H NMR spectroscopy of biological fluids. , 1996, Analytical chemistry.

[62]  Elaine Holmes,et al.  Metabonomics technologies and their applications in physiological monitoring, drug safety assessment and disease diagnosis , 2004, Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals.

[63]  Jan van der Greef,et al.  A pilot study to investigate effects of inulin on Caco-2 cells through in vitro metabolic fingerprinting. , 2003, The Journal of nutrition.

[64]  K. E. Price,et al.  Tissue targeted metabonomics: metabolic profiling by microdialysis sampling and microcoil NMR. , 2005, Journal of pharmaceutical and biomedical analysis.

[65]  I. Wilson,et al.  Understanding 'Global' Systems Biology: Metabonomics and the Continuum of Metabolism , 2003, Nature Reviews Drug Discovery.

[66]  Ben van Ommen,et al.  Profiles of Metabolites and Gene Expression in Rats with Chemically Induced Hepatic Necrosis , 2005, Toxicologic pathology.

[67]  Jennifer H Granger,et al.  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. , 2005, The Analyst.

[68]  Ian D. Wilson,et al.  HIGH RESOLUTION PROTON MAGNETIC RESONANCE SPECTROSCOPY OF BIOLOGICAL FLUIDS , 1989 .

[69]  M. Spraul,et al.  High resolution magic angle spinning 1H nuclear magnetic resonance analysis of intact prostatic hyperplastic and tumour tissues , 1998 .

[70]  B. Sitter,et al.  High‐resolution magic angle spinning MRS of breast cancer tissue , 2002, NMR in biomedicine.

[71]  J Bruce German,et al.  Genomics and metabolomics as markers for the interaction of diet and health: lessons from lipids. , 2003, The Journal of nutrition.