Metabolomics in Systems Toxicology: Towards Personalized Medicine

Metabolomics along with systems biology technologies such as transcriptomics and proteomics has the capability of providing translational diagnostic, prognostic and mechanistic biomarkers of drug-induced injury. Metabolomics has several advantages over the other omics platforms, such as ease of sample preparation, data acquisition and use of biofluids collected through minimally invasive procedures in pre-clinical and clinical studies. The role of metabolomics in systems toxicology is reviewed and examples of metabolomics in pre-clinical and clinical studies are provided. The role of metabolomics in personalized medicine is provided with special sections focusing on drug–drug and drug–nutrient interactions, metabolic fluxes and challenge tests. Keywords: metabolomics; metabonomics; metabolic fluxes; biomarkers; personalized medicine; systems biology

[1]  M. Comporti Glutathione depleting agents and lipid peroxidation. , 1987, Chemistry and physics of lipids.

[2]  J. Klawitter,et al.  Abnormalities in Glucose Uptake and Metabolism in Imatinib-Resistant Human BCR-ABL–Positive Cells , 2009, Clinical Cancer Research.

[3]  J. German,et al.  Assessing individual metabolic responsiveness to a lipid challenge using a targeted metabolomic approach , 2008, Metabolomics.

[4]  H. Jaeschke,et al.  The role of oxidant stress and reactive nitrogen species in acetaminophen hepatotoxicity. , 2003, Toxicology letters.

[5]  Huifeng Wu,et al.  Metabolic profiling studies on the toxicological effects of realgar in rats by (1)H NMR spectroscopy. , 2009, Toxicology and applied pharmacology.

[6]  D. Thompson,et al.  Role of Metabolism in Drug-Induced Idiosyncratic Hepatotoxicity , 2005, Critical reviews in toxicology.

[7]  Oliver Fiehn,et al.  Plant Metabolomics , 2002, The Plant Cell Online.

[8]  Oliver Fiehn,et al.  Combining Genomics, Metabolome Analysis, and Biochemical Modelling to Understand Metabolic Networks , 2001, Comparative and functional genomics.

[9]  O. Arrigoni,et al.  Ascorbic acid: much more than just an antioxidant. , 2002, Biochimica et biophysica acta.

[10]  Y. Moon,et al.  Dietary flavonoids: effects on xenobiotic and carcinogen metabolism. , 2006, Toxicology in vitro : an international journal published in association with BIBRA.

[11]  M. Cascante,et al.  The Stable Isotope-based Dynamic Metabolic Profile of Butyrate-induced HT29 Cell Differentiation* , 2003, Journal of Biological Chemistry.

[12]  L. Boros,et al.  SiDMAP: a metabolomics approach to assess the effects of drug candidates on the dynamic properties of biochemical pathways , 2006, Expert opinion on drug discovery.

[13]  H. Tokuno,et al.  Changes in the rates of the tricarboxylic acid (TCA) cycle and glutamine synthesis in the monkey brain with hemiparkinsonism induced by intracarotid infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): Studies by non-invasive 13C-magnetic resonance spectroscopy , 2007, Brain Research.

[14]  R. Beger,et al.  Monitoring the health to disease continuum with global metabolic profiling and systems biology. , 2006, Pharmacogenomics.

[15]  Weida Tong,et al.  An integrated study of acute effects of valproic acid in the liver using metabonomics, proteomics, and transcriptomics platforms. , 2006, Omics : a journal of integrative biology.

[16]  P. Kris-Etherton,et al.  How does MyPyramid compare to other population-based recommendations for controlling chronic disease? , 2007, Journal of the American Dietetic Association.

[17]  Yi-Xiang J. Wang,et al.  Biomedical Imaging in the Safety Evaluation of New Drugs , 2022 .

[18]  L. Boros,et al.  Single valproic acid treatment inhibits glycogen and RNA ribose turnover while disrupting glucose-derived cholesterol synthesis in liver as revealed by the [U-13C6]-d-glucose tracer in mice , 2009, Metabolomics.

[19]  M. Filipič,et al.  Alteration of intracellular GSH levels and its role in microcystin-LR-induced DNA damage in human hepatoma HepG2 cells. , 2006, Mutation research.

[20]  F. Frueh,et al.  Biomarker qualification pilot process at the US Food and Drug Administration , 2007, The AAPS Journal.

[21]  Halka Lotková,et al.  S-Adenosylmethionine Exerts a Protective Effect against Thioacetamide-induced Injury in Primary Cultures of Rat Hepatocytes , 2007, Alternatives to laboratory animals : ATLA.

[22]  P. Whitfield,et al.  Horizons in Nutritional Science Metabolomics: an emerging post-genomic tool for nutrition , 2004 .

[23]  R. Ulrich,et al.  Idiosyncratic toxicity: a convergence of risk factors. , 2007, Annual review of medicine.

[24]  Laura K. Schnackenberg,et al.  The Liver Toxicity Biomarker Study: Phase I Design and Preliminary Results , 2009, Toxicologic pathology.

[25]  Alison A Motsinger,et al.  Multifactor dimensionality reduction: An analysis strategy for modelling and detecting gene - gene interactions in human genetics and pharmacogenomics studies , 2006, Human Genomics.

[26]  Diagnosis of inborn errors of metabolism using 1H NMR spectroscopic analysis of urine , 1999, Journal of Inherited Metabolic Disease.

[27]  Wei Duan,et al.  Herb-Drug Interactions , 2012, Drugs.

[28]  Richard D Beger,et al.  Metabonomics evaluation of urine from rats given acute and chronic doses of acetaminophen using NMR and UPLC/MS. , 2008, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[29]  U. Christians,et al.  Biomarkers for Toxicodynamic Monitoring of Immunosuppressants: NMR-Based Quantitative Metabonomics of the Blood , 2005, Therapeutic drug monitoring.

[30]  Michael D. Waters,et al.  Toxicogenomics and systems toxicology: aims and prospects , 2004, Nature Reviews Genetics.

[31]  S. Ross Nutritional genomic approaches to cancer prevention research. , 2007, Experimental oncology.

[32]  Anthony F. P. Nash,et al.  A 1H NMR-based metabonomic study of urine and plasma samples obtained from healthy human subjects. , 2003, Journal of pharmaceutical and biomedical analysis.

[33]  J. Nicholson,et al.  Integrated metabonomic analysis of the multiorgan effects of hydrazine toxicity in the rat. , 2005, Chemical research in toxicology.

[34]  Marta Cascante,et al.  Dynamic profiling of the glucose metabolic network in fasted rat hepatocytes using [1,2-13C2]glucose. , 2004, The Biochemical journal.

[35]  Richard D Beger,et al.  Differential gene expression in mouse liver associated with the hepatoprotective effect of clofibrate. , 2007, Toxicology and applied pharmacology.

[36]  L. Lynd,et al.  Risk of Warfarin‐Related Bleeding Events and Supratherapeutic International Normalized Ratios Associated with Complementary and Alternative Medicine: A Longitudinal Analysis , 2007, Pharmacotherapy.

[37]  Y. Nikolsky,et al.  Nutrigenomics: concepts and applications to pharmacogenomics and clinical medicine. , 2007, Pharmacogenomics.

[38]  Vilmundur Gudnason,et al.  A variant of the gene encoding leukotriene A4 hydrolase confers ethnicity-specific risk of myocardial infarction , 2006, Nature Genetics.

[39]  J. Suttie Warfarin and vitamin K. , 1990, Clinical cardiology.

[40]  J. McMillan,et al.  S-adenosylmethionine but not glutathione protects against galactosamine-induced cytotoxicity in rat hepatocyte cultures. , 2006, Toxicology.

[41]  J. Uetrecht,et al.  Mechanism of idiosyncratic drug reactions: reactive metabolite formation, protein binding and the regulation of the immune system. , 2002, Current drug metabolism.

[42]  D. A. Gorard,et al.  Escalating polypharmacy. Commentary , 2006 .

[43]  A. Smilde,et al.  Metabolic Profiling of the Response to an Oral Glucose Tolerance Test Detects Subtle Metabolic Changes , 2009, PloS one.

[44]  J. Griffin,et al.  Cellular environment of metabolites and a metabonomic study of tamoxifen in endometrial cells using gradient high resolution magic angle spinning 1H NMR spectroscopy. , 2003, Biochimica et biophysica acta.

[45]  H. Woo,et al.  Metabolomic approach to evaluate the toxicological effects of nonylphenol with rat urine. , 2007, Analytical chemistry.

[46]  S. Stürzenbaum,et al.  'Systems toxicology' approach identifies coordinated metabolic responses to copper in a terrestrial non-model invertebrate, the earthworm Lumbricus rubellus , 2008, BMC Biology.

[47]  Jeremiah Stamler,et al.  Detection of urinary drug metabolite (xenometabolome) signatures in molecular epidemiology studies via statistical total correlation (NMR) spectroscopy. , 2007, Analytical chemistry.

[48]  P. Kubler,et al.  Aminoglycoside-associated Fanconi syndrome. , 2006, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[49]  Jun Zhang,et al.  The utility of a rodent model in detecting pediatric drug-induced nephrotoxicity. , 2007, Toxicological sciences : an official journal of the Society of Toxicology.

[50]  T. Ajith,et al.  Ascorbic acid and alpha-tocopherol protect anticancer drug cisplatin induced nephrotoxicity in mice: a comparative study. , 2007, Clinica chimica acta; international journal of clinical chemistry.

[51]  E Holmes,et al.  Metabonomic investigations into hydrazine toxicity in the rat. , 2001, Chemical research in toxicology.

[52]  Erik J Martin,et al.  Mitochondrial Dysfunction Is an Early Manifestation of 1,1-Dichloroethylene-Induced Hepatotoxicity in Mice , 2003, Journal of Pharmacology and Experimental Therapeutics.

[53]  N. Vermeulen,et al.  Paracetamol (Acetaminophen)-Induced Toxicity: Molecular and Biochemical Mechanisms, Analogues and Protective Approaches , 2001, Critical reviews in toxicology.

[54]  P. Hollman,et al.  Absorption, metabolism and health effects of dietary flavonoids in man. , 1997, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[55]  N. Kaplowitz,et al.  Mechanisms of liver injury. III. Role of glutathione redox status in liver injury. , 2006, American journal of physiology. Gastrointestinal and liver physiology.

[56]  Johan Trygg,et al.  Chemometrics in metabonomics. , 2007, Journal of proteome research.

[57]  S. Booth,et al.  Vitamin K: a practical guide to the dietary management of patients on warfarin. , 2009, Nutrition reviews.

[58]  N. Serkova,et al.  Biochemical mechanisms of nephrotoxicity: application for metabolomics , 2007 .

[59]  I. Wilson,et al.  Gut microorganisms, mammalian metabolism and personalized health care , 2005, Nature Reviews Microbiology.

[60]  George G Harrigan,et al.  Metabolic biomarker and kinase drug target discovery in cancer using stable isotope-based dynamic metabolic profiling (SIDMAP). , 2003, Current cancer drug targets.

[61]  R. Recker,et al.  Quantitative proteomics: measuring protein synthesis using 15N amino acid labeling in pancreatic cancer cells. , 2009, Analytical chemistry.

[62]  I. Wilson,et al.  Metabonomics, dietary influences and cultural differences: a 1H NMR-based study of urine samples obtained from healthy British and Swedish subjects. , 2004, Journal of pharmaceutical and biomedical analysis.

[63]  S. Eckhardt,et al.  Clinical Applications of Metabolomics in Oncology: A Review , 2009, Clinical Cancer Research.

[64]  M. Matsumoto,et al.  Undesirable Effects of Citrus Juice on the Pharmacokinetics of Drugs , 2005, Drug safety.

[65]  David S. Wishart,et al.  Quantitative metabolomics using NMR , 2008 .

[66]  D. Phillips,et al.  A steep increase in domestic fatal medication errors with use of alcohol and/or street drugs. , 2008, Archives of internal medicine.

[67]  G. Merli,et al.  Vitamin K and thrombosis. , 2008, Vitamins and hormones.

[68]  Y. Dragan,et al.  Evaluation of NMR spectral data of urine in conjunction with measured clinical chemistry and histopathology parameters to assess the effects of liver and kidney toxicants , 2007, Metabolomics.

[69]  John Milner,et al.  Nutrigenomics, proteomics, metabolomics, and the practice of dietetics. , 2006, Journal of the American Dietetic Association.

[70]  G. Stoner,et al.  Comparison of phenethyl and 6-phenylhexyl isothiocyanate-induced toxicity in rat esophageal cell lines with and without glutathione depletion. , 2005, Toxicology letters.

[71]  G. Lombardi,et al.  Presence of Kynurenic Acid in the Mammalian Brain , 1988, Journal of neurochemistry.

[72]  T. Hankemeier,et al.  Metabolomics-based systems biology and personalized medicine: moving towards n = 1 clinical trials? , 2006, Pharmacogenomics.

[73]  M. Reily,et al.  Metabonomic assessment of vasculitis in rats , 2007, Cardiovascular Toxicology.

[74]  R. Recker,et al.  Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. , 2007, The American journal of clinical nutrition.

[75]  W. Stahl,et al.  Antioxidant Functions of Vitamins , 1992, Annals of the New York Academy of Sciences.

[76]  Angelo A. Izzo,et al.  Interactions Between Herbal Medicines and Prescribed Drugs , 2012, Drugs.

[77]  J. Senior,et al.  Drug-related hepatotoxicity. , 2006, The New England journal of medicine.

[78]  Huifeng Wu,et al.  Toxicological effects of cinnabar in rats by NMR-based metabolic profiling of urine and serum. , 2008, Toxicology and applied pharmacology.

[79]  Jean-Daniel Zucker,et al.  Horizons in nutritional science : The case for strategic international alliances to harness nutritional genomics for public and personal health. , 2005 .

[80]  Mark D Shriver,et al.  Measuring European population stratification with microarray genotype data. , 2007, American journal of human genetics.

[81]  E. Kennedy Evidence for nutritional benefits in prolonging wellness. , 2006, The American journal of clinical nutrition.

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

[83]  E. Sellers,et al.  Drug Kinetics and Alcohol Ingestion , 1978, Clinical pharmacokinetics.

[84]  G. Zaccara,et al.  Idiosyncratic Adverse Reactions to Antiepileptic Drugs , 2007, Epilepsia.

[85]  H. Krebs,et al.  The redox state of free nicotinamide-adenine dinucleotide phosphate in the cytoplasm of rat liver. , 1969, The Biochemical journal.

[86]  Howard Cabral,et al.  Weight, Blood Pressure, and Dietary Benefits After 12 Months of a Web-based Nutrition Education Program (DASH for Health): Longitudinal Observational Study , 2008, Journal of medical Internet research.

[87]  Oliver Fiehn,et al.  Mass-spectrometry-based metabolomics: limitations and recommendations for future progress with particular focus on nutrition research , 2009, Metabolomics.

[88]  Leo L. Cheng,et al.  NMR-based metabolomics approach to target biomarkers for human prostate cancer , 2007, Expert review of proteomics.

[89]  L. Quattrochi,et al.  Differential effects of flavonoid compounds on tumor promoter-induced activation of the human CYP1A2 enhancer. , 2000, Archives of biochemistry and biophysics.

[90]  B. Ali,et al.  Agents ameliorating or augmenting the nephrotoxicity of cisplatin and other platinum compounds: a review of some recent research. , 2006, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[91]  D. Nebert,et al.  Pharmacogenomics and “Individualized Drug Therapy” , 2003 .

[92]  Ben van Ommen,et al.  Toxicogenomics of bromobenzene hepatotoxicity: a combined transcriptomics and proteomics approach. , 2003, Biochemical pharmacology.

[93]  A. Drewnowski,et al.  Does aging change nutrition requirements? , 2001, The Journal of Nutrition, Health & Aging.

[94]  Andrew W Nicholls,et al.  Personalized medicine progresses , 2006, Nature Medicine.

[95]  Abraham Nyska,et al.  Discovery of Metabolomics Biomarkers for Early Detection of Nephrotoxicity , 2009, Toxicologic pathology.

[96]  S. Callegari-Jacques,et al.  Application of an African Ancestry Index as a Genomic Control Approach in a Brazilian Population , 2006, Annals of human genetics.

[97]  Ian D. Wilson,et al.  Metabolic Phenotyping in Health and Disease , 2008, Cell.

[98]  C. Richelme,et al.  Abnormal α-aminoadipic acid excretion in a newborn with a defect in platelet aggregation and antenatal cerebral haemorrhage , 1995, Journal of Inherited Metabolic Disease.

[99]  D E Bauman,et al.  The nutritional phenotype in the age of metabolomics. , 2005, The Journal of nutrition.

[100]  O. Fiehn,et al.  Metabolite profiling for plant functional genomics , 2000, Nature Biotechnology.

[101]  J. van der Greef,et al.  Systems biology, connectivity and the future of medicine. , 2005 .

[102]  R. Rivlin Keeping the young-elderly healthy: is it too late to improve our health through nutrition? , 2007, The American journal of clinical nutrition.

[103]  D. Dorman,et al.  Metabolomic analyses of body fluids after subchronic manganese inhalation in rhesus monkeys. , 2008, Toxicological sciences : an official journal of the Society of Toxicology.

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

[105]  N. Sultana,et al.  Grape fruit juice-drug interactions. , 2005, Pakistan journal of pharmaceutical sciences.

[106]  S. Pyke,et al.  Strong Protein Adduct Trapping Accompanies Abolition of Acrolein-Mediated Hepatotoxicity by Hydralazine in Mice , 2004, Journal of Pharmacology and Experimental Therapeutics.

[107]  Ben van Ommen,et al.  Bromobenzene-induced hepatotoxicity at the transcriptome level. , 2004, Toxicological sciences : an official journal of the Society of Toxicology.

[108]  E. Schiff,et al.  Acetaminophen safety and hepatotoxicity – where do we go from here? , 2007, Expert opinion on drug safety.

[109]  Elaine Holmes,et al.  Prediction and classification of drug toxicity using probabilistic modeling of temporal metabolic data: the consortium on metabonomic toxicology screening approach. , 2007, Journal of proteome research.

[110]  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.

[111]  C. Leonetti,et al.  α‐tocopherol protects against cisplatin‐induced toxicity without interfering with antitumor efficacy , 2003, International journal of cancer.

[112]  B. Mckevith Diet and healthy ageing , 2005, The journal of the British Menopause Society.

[113]  C. Dejong,et al.  Renal metabolism of amino acids: its role in interorgan amino acid exchange. , 2004, The American journal of clinical nutrition.

[114]  G. Dresser,et al.  Grapefruit‐felodipine interaction: Effect of unprocessed fruit and probable active ingredients , 2000, Clinical pharmacology and therapeutics.

[115]  R. Salganik The Benefits and Hazards of Antioxidants: Controlling Apoptosis and Other Protective Mechanisms in Cancer Patients and the Human Population , 2001, Journal of the American College of Nutrition.

[116]  U. Klotz,et al.  Influence of Diet and Nutritional Status on Drug Metabolism , 1996, Clinical pharmacokinetics.

[117]  G. Block,et al.  A rapid food screener to assess fat and fruit and vegetable intake. , 2000, American journal of preventive medicine.

[118]  D. Sica Interaction of grapefruit juice and calcium channel blockers. , 2006, American journal of hypertension.

[119]  Wolfgang Völkel,et al.  Metabonomics and biomarker discovery: LC-MS metabolic profiling and constant neutral loss scanning combined with multivariate data analysis for mercapturic acid analysis. , 2006, Analytical chemistry.

[120]  M. Murray Altered CYP expression and function in response to dietary factors: potential roles in disease pathogenesis. , 2006, Current drug metabolism.

[121]  S. Wagner,et al.  Tools in metabonomics: an integrated validation approach for LC-MS metabolic profiling of mercapturic acids in human urine. , 2007, Analytical chemistry.

[122]  P. Elliott,et al.  Assessment of analytical reproducibility of 1H NMR spectroscopy based metabonomics for large-scale epidemiological research: the INTERMAP Study. , 2006, Analytical chemistry.

[123]  Julian L Griffin,et al.  Metabonomics: NMR spectroscopy and pattern recognition analysis of body fluids and tissues for characterisation of xenobiotic toxicity and disease diagnosis. , 2003, Current opinion in chemical biology.

[124]  Liping Zhao,et al.  Pharmacometabonomic phenotyping reveals different responses to xenobiotic intervention in rats. , 2007, Journal of proteome research.

[125]  E. Herman,et al.  Age‐related differences in susceptibility to toxic effects of valproic acid in rats , 2008, Journal of applied toxicology : JAT.

[126]  Jason E. Stewart,et al.  Minimum information about a microarray experiment (MIAME)—toward standards for microarray data , 2001, Nature Genetics.

[127]  R. Beger,et al.  Studies of acetaminophen and metabolites in urine and their correlations with toxicity using metabolomics. , 2009, Drug metabolism letters.

[128]  H. Lee,et al.  Pattern recognition analysis for the prediction of adverse effects by nonsteroidal anti-inflammatory drugs using 1H NMR-based metabolomics in rats. , 2009, Analytical chemistry.

[129]  G. Dresser,et al.  Bergamottin, lime juice, and red wine as inhibitors of cytochrome P450 3A4 activity: Comparison with grapefruit juice , 2003, Clinical pharmacology and therapeutics.

[130]  D. Kell Systems biology, metabolic modelling and metabolomics in drug discovery and development. , 2006, Drug discovery today.

[131]  K. Mohanakumar,et al.  Melatonin protects against rotenone‐induced oxidative stress in a hemiparkinsonian rat model , 2007, Journal of pineal research.

[132]  Ivano Bertini,et al.  Evidence of different metabolic phenotypes in humans , 2008, Proceedings of the National Academy of Sciences.

[133]  Hector Keun,et al.  COMET and the challenge of drug safety screening. , 2007, Journal of proteome research.

[134]  B. Pollock,et al.  Bupropion plasma levels and CYP2D6 phenotype. , 1996, Therapeutic drug monitoring.

[135]  Donald G Robertson,et al.  Metabonomics in toxicology: a review. , 2005, Toxicological sciences : an official journal of the Society of Toxicology.

[136]  Nigel W. Hardy,et al.  The Metabolomics Standards Initiative , 2007, Nature Biotechnology.

[137]  T. Hartung,et al.  A novel in vitro metabolomics approach for neurotoxicity testing, proof of principle for methyl mercury chloride and caffeine. , 2008, Neurotoxicology.

[138]  M. Reily,et al.  Effect of dexamethasone on the metabonomics profile associated with phosphodiesterase inhibitor-induced vascular lesions in rats. , 2002, Toxicology and applied pharmacology.

[139]  D. Nebert,et al.  Advances in pharmacogenomics and individualized drug therapy: exciting challenges that lie ahead. , 2004, European journal of pharmacology.

[140]  J. Nicholson,et al.  Application of chemometrics to 1H NMR spectroscopic data to investigate a relationship between human serum metabolic profiles and hypertension. , 2003, The Analyst.

[141]  E. Schleicher,et al.  Changes of the plasma metabolome during an oral glucose tolerance test: is there more than glucose to look at? , 2009, American journal of physiology. Endocrinology and metabolism.

[142]  M. Lerner,et al.  [1,2-13C2]-D-Glucose Profiles of the Serum, Liver, Pancreas, and DMBA-Induced Pancreatic Tumors of Rats , 2005, Pancreas.

[143]  J. Kaput,et al.  Challenging homeostasis to define biomarkers for nutrition related health. , 2009, Molecular nutrition & food research.

[144]  William M. Lee Acetaminophen and the U.S. acute liver failure study group: Lowering the risks of hepatic failure , 2004, Hepatology.

[145]  D. Wishart Metabolomics: a complementary tool in renal transplantation. , 2008, Contributions to nephrology.

[146]  Eun-Young Kim,et al.  A Metabonomic Study on the Biochemical Effects of Doxorubicin in Rats Using 1H-NMR Spectroscopy , 2009, Journal of toxicology and environmental health. Part A.

[147]  Martin Kussmann,et al.  OMICS-driven biomarker discovery in nutrition and health. , 2006, Journal of biotechnology.

[148]  L. Boros,et al.  PNU-91325 increases fatty acid synthesis from glucose and mitochondrial long chain fatty acid degradation: a comparative tracer-based metabolomics study with rosiglitazone and pioglitazone in HepG2 cells , 2006, Metabolomics.

[149]  Elaine Holmes,et al.  Systems toxicology: integrated genomic, proteomic and metabonomic analysis of methapyrilene induced hepatotoxicity in the rat. , 2006, Journal of proteome research.

[150]  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.

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

[152]  J. Wang,et al.  Role of taurine in preventing acetaminophen-induced hepatic injury in the rat. , 2001, American journal of physiology. Gastrointestinal and liver physiology.

[153]  D E Bauman,et al.  Metabolomics in the opening decade of the 21st century: building the roads to individualized health. , 2004, The Journal of nutrition.

[154]  Griffin Jl,et al.  Metabonomics: its potential as a tool in toxicology for safety assessment and data integration. , 2004 .

[155]  D. Hunkler,et al.  Possibilities of selective screening for inborn errors of metabolism using high-resolution 1H-FT-NMR spectrometry , 1986, European Journal of Pediatrics.

[156]  J. Nicholson,et al.  Rapid and noninvasive diagnosis of the presence and severity of coronary heart disease using 1H-NMR-based metabonomics , 2002, Nature Medicine.

[157]  G. Jang,et al.  Dietary Effects on Drug Metabolism and Transport , 2003, Clinical pharmacokinetics.

[158]  H. Baker Nutrition in the elderly: An overview. , 2007, Geriatrics.

[159]  Jeremy K Nicholson,et al.  Use of metabonomics to identify impaired fatty acid metabolism as the mechanism of a drug-induced toxicity. , 2004, Chemical research in toxicology.

[160]  J. Haselden,et al.  Metabolic Profiling as a Tool for Understanding Mechanisms of Toxicity , 2008, Toxicologic pathology.

[161]  W. Tong,et al.  Evaluations of the trans-sulfuration pathway in multiple liver toxicity studies. , 2009, Toxicology and applied pharmacology.

[162]  Z. Djuric,et al.  Effect of Varying Dietary Fat Levels on Rat Growth and Oxidative DNA Damage , 2001, Nutrition and cancer.

[163]  John C Lindon,et al.  Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism , 2009, Proceedings of the National Academy of Sciences.

[164]  J. Milner,et al.  Molecular targets for bioactive food components. , 2004, The Journal of nutrition.

[165]  Emmanuel Mikros,et al.  Application of nuclear magnetic resonance spectroscopy combined with principal component analysis in detecting inborn errors of metabolism using blood spots: a metabonomic approach , 2004 .

[166]  D. Chace,et al.  The application of tandem mass spectrometry to neonatal screening for inherited disorders of intermediary metabolism. , 2002, Annual review of genomics and human genetics.

[167]  D. Putt,et al.  Role of mitochondrial dysfunction in cellular responses to S-(1,2-dichlorovinyl)-L-cysteine in primary cultures of human proximal tubular cells. , 2008, Biochemical pharmacology.

[168]  J. Megyesi,et al.  Metabolomic study of cisplatin-induced nephrotoxicity. , 2006, Kidney international.