Skip to main content
SpringerLink
Log in

LC–MS-based metabolomics: an update

  • Review Article
  • Published:
Archives of Toxicology Aims and scope Submit manuscript

Abstract

Liquid chromatography–mass spectrometry (LC–MS)-based metabolomics can have a major impact in multiple research fields, especially when combined with other technologies, such as stable isotope tracers and genetically modified mice. This review highlights recent applications of metabolomic technology in the study of xenobiotic metabolism and toxicity, and the understanding of disease pathogenesis and therapeutics. Metabolomics has been employed to study metabolism of noscapine, an aryl hydrocarbon receptor antagonist, and to determine the mechanisms of liver toxicities of rifampicin and isoniazid, trichloroethylene, and gemfibrozil. Metabolomics-based insights into the pathogenesis of inflammatory bowel disease, alcohol-induced liver diseases, non-alcoholic steatohepatitis, and farnesoid X receptor signaling pathway-based therapeutic target discovery will also be discussed. Limitations in metabolomics technology such as sample preparation and lack of LC–MS databases and metabolite standards, need to be resolved in order to improve and broaden the application of metabolomic studies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

APAP:

Acetaminophen

ALAS:

Aminolevulinic acid synthase

AHR:

Aryl hydrocarbon receptor

BSH:

Bile salt hydrolase

CES3:

Carboxylesterase 3

CYP:

Cytochrome P450

CVD:

Cardiovascular diseases

DSS:

Dextran sulfate sodium

DCA:

Dichloroacetate

DRE:

Dioxin response elements

FXR:

Farnesoid X receptor

GC–MS:

Gas chromatography–mass spectrometry

GVHD:

Graft-versus-host disease

IBD:

Inflammatory bowel disease

INH:

Isoniazid

LC–MS:

Liquid chromatography–mass spectrometry

LPC:

Lysophosphatidylcholine

GNF351:

N-(2-(1H-Indol-3-yl)ethyl)-9-isopropyl-2-(5-methylpyridin-3-yl)-9H-purin-6-amine

NASH:

Non-alcoholic steatohepatitis

PPARα:

Peroxisome proliferator-activated receptor α

PC:

Phosphatidylcholine

PCA:

Principle components analysis

PCOS:

Polycystic ovary syndrome

PXR:

Pregnane X receptor

1H NMR:

Proton nuclear magnetic resonance

PPIX:

Protoporphyrin IX

RIF:

Rifampicin

SCD1:

Stearoyl-CoA desaturase 1

TβMCA:

Tauro-β-muricholic acid

TNBS:

Trinitrobenzene sulfonic acid

TCA:

Trichloroacetate

TCE:

Trichloroethylene

VDR:

Vitamin D receptor

References

  • Aneja R, Katyal A, Chandra R (2004) Modulatory influence of noscapine on the ethanol-altered hepatic biotransformation system enzymes, glutathione content and lipid peroxidation in vivo in rats. Eur J Drug Metab Pharmacokinet 29:157–162

    Article  CAS  PubMed  Google Scholar 

  • Bakke B, Stewart PA, Waters MA (2007) Uses of and exposure to trichloroethylene in US industry: a systematic literature review. J Occup Environ Hyg 4:375–390

    Article  CAS  PubMed  Google Scholar 

  • Bujak R, Garcia-Alvarez A, Ruperez FJ et al (2014) Metabolomics reveals metabolite changes in acute pulmonary embolism. J Proteome Res. doi:10.1021/pr400872j

    PubMed  Google Scholar 

  • Castro-Perez JM, Roddy TP, Shah V et al (2011) Attenuation of Slc27a5 gene expression followed by LC–MS measurement of bile acid reconjugation using metabolomics and a stable isotope tracer strategy. J Proteome Res 10:4683–4691

    Article  CAS  PubMed  Google Scholar 

  • Chen C, Gonzalez FJ, Idle JR (2007) LC–MS-based metabolomics in drug metabolism. Drug Metab Rev 39(2–3):581–597

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chen C, Krausz KW, Idle JR, Gonzalez FJ (2008a) Identification of novel toxicity-associated metabolites by metabolomics and mass isotopomer analysis of acetaminophen metabolism in wild-type and Cyp2e1-null mice. J Biol Chem 283:4543–4559

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chen C, Shah YM, Morimura K et al (2008b) Metabolomics reveals that hepatic stearoyl-CoA desaturase 1 downregulation exacerbates inflammation and acute colitis. Cell Metab 7:135–147

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chen M, Zhou K, Chen X et al (2014) Metabolomic analysis reveals metabolic changes caused by bisphenol A in rats. Toxicol Sci. doi:10.1093/toxsci/kfu016

    Google Scholar 

  • Cheng J, Shah YM, Ma XC et al (2010) Therapeutic role of rifaximin in inflammatory bowel disease: clinical implication of human pregnane X Receptor activation. J Pharmacol Exp Ther 335:32–41

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Cheng J, Krausz KW, Tanaka N, Gonzalez FJ (2012) Chronic exposure to rifaximin causes hepatic steatosis in pregnane X receptor-humanized mice. Toxicol Sci 129:456–468

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Cheng J, Krausz KW, Li F, Ma XC, Gonzalez FJ (2013) CYP2E1-dependent elevation of serum cholesterol, triglycerides, and hepatic bile acids by isoniazid. Toxicol Appl Pharm 266:245–253

    Article  CAS  Google Scholar 

  • Cheng J, Fang ZZ, Kim JH, Krausz KW, Tanaka N, Chiang JY, Gonzalez FJ (2014) Intestinal CYP3A4 protects against lithocholic acid-induced hepatotoxicity in vitamin D receptor intestine-deficient mice. J Lipid Res 55:455–465

    Article  CAS  PubMed  Google Scholar 

  • Dumas ME, Kinross J, Nicholson JK (2014) Metabolic phenotyping and systems biology approaches to understanding metabolic syndrome and fatty liver disease. Gastroenterology 146:46–62

    Article  PubMed  Google Scholar 

  • Duportet X, Aggio RBM, Carneiro S, Villas-Boas SG (2012) The biological interpretation of metabolomic data can be misled by the extraction method used. Metabolomics 8:410–421

    Article  CAS  Google Scholar 

  • Espina R, Yu LN, Wang JY et al (2009) Nuclear magnetic resonance spectroscopy as a quantitative tool to determine the concentrations of biologically produced metabolites: implications in metabolites in safety testing. Chem Res Toxicol 22:299–310

    Article  CAS  PubMed  Google Scholar 

  • Evans CR, Karnovsky A, Kovach MA, Standiford TJ, Burant CF, Stringer KA (2013) Untargeted LC-MS metabolomics of bronchoalveolar lavage fluid differentiates acute respiratory distress syndrome from health. J Proteome Res. doi:10.1021/pr4007624

    PubMed  Google Scholar 

  • Fang ZZ, Zhang YY, Ge GB, Huo H, Liang SC, Yang L (2010) Time-dependent inhibition (TDI) of CYP3A4 and CYP2C9 by noscapine potentially explains clinical noscapine-warfarin interaction. Br J Clin Pharmacol 69:193–199

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Fang ZZ, Krausz KW, Li F, Cheng J, Tanaka N, Gonzalez FJ (2012) Metabolic map and bioactivation of the anti-tumour drug noscapine. Br J Pharmacol 167:1271–1286

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Fang ZZ, Krausz KW, Tanaka N et al (2013) Metabolomics reveals trichloroacetate as a major contributor to trichloroethylene-induced metabolic alterations in mouse urine and serum. Arch Toxicol 87:1975–1987

    Article  CAS  PubMed  Google Scholar 

  • Fang ZZ, Krausz KW, Nagaoka K et al (2014) In vivo application of the pure aryl hydrocarbon receptor antagonist GNF-351 is limited to the gastrointestinal track. Br J Pharmacol 171:1735–1746

    Article  CAS  PubMed  Google Scholar 

  • Go YM, Roede JR, Orr M, Liang Y, Jones DP (2014) Integrated redox proteomics and metabolomics of mitochondria to identify mechanisms of Cd toxicity. Toxicol Sci 171:1735–1746

    Google Scholar 

  • Gonzalez-Dominguez R, Garcia-Barrera T, Gomez-Ariza JL (2014) Combination of metabolomic and phospholipid-profiling approaches for the study of Alzheimer’s disease. J Proteomics. doi:10.1016/j.jprot.2014.01.014

    PubMed  Google Scholar 

  • Hong EJ, Levasseur MP, Dufour CR, Perry MC, Giguere V (2013) Loss of estrogen-related receptor a promotes hepatocarcinogenesis development via metabolic and inflammatory disturbances. Proc Natl Acad Sci USA 110:17975–17980

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Jansen RS, Kucukosmanoglu A, de Haas M et al (2013) ABCC6 prevents ectopic mineralization seen in pseudoxanthoma elasticum by inducing cellular nucleotide release. Proc Natl Acad Sci USA 110:20206–20211

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Jiang LM, Huang J, Wang YL, Tang HR (2012) Metabonomic analysis reveals the CCl4-Induced systems alterations for multiple rat organs. J Proteome Res 11:3848–3859

    Article  CAS  PubMed  Google Scholar 

  • Johnson CH, Gonzalez FJ (2012) Challenges and opportunities of metabolomics. J Cell Phys 227:2975–2981

    Article  CAS  Google Scholar 

  • Johnson CH, Patterson AD, Idle JR, Gonzalez FJ (2012a) Xenobiotic metabolomics: major impact on the metabolome. Annu Rev Pharmacol 52:37–56

    Article  CAS  Google Scholar 

  • Johnson CH, Slanar O, Krausz KW et al (2012b) Novel metabolites and roles for alpha-tocopherol in humans and mice discovered by mass spectrometry-based metabolomics. Am J Clin Nutr 96:818–830

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kim JH, Yamaori S, Tanabe T et al (2013) Implication of intestinal VDR deficiency in inflammatory bowel disease. Bba-Gen Subj 1830:2118–2128

    Article  CAS  Google Scholar 

  • Lane AN, Fan TWM, Bousamra M, Higashi RM, Yan J, Miller DM (2011) Stable isotope-resolved metabolomics (SIRM) in cancer research with clinical application to non-small cell lung cancer. OMICS 15:173–182

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Leichtle AB, Nuoffer JM, Ceglarek U et al (2012) Serum amino acid profiles and their alterations in colorectal cancer. Metabolomics 8:643–653

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Li F, Miao Y, Zhang LR, Neuenswander SA, Douglas JT, Ma XC (2011) Metabolomic analysis reveals novel isoniazid metabolites and hydrazones in human urine. Drug Metab Pharmacok 26:569–576

    Article  CAS  Google Scholar 

  • Li F, Patterson AD, Krausz KW et al (2012) Metabolomics reveals the metabolic map of procainamide in humans and mice. Biochem Pharmacol 83:1435–1444

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Li F, Jiang CT, Krausz KW et al (2013a) Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity. Nat Commun 4:2384

    PubMed  Google Scholar 

  • Li F, Lu J, Cheng J et al (2013b) Human PXR modulates hepatotoxicity associated with rifampicin and isoniazid co-therapy. Nat Med 19:418–420

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Li F, Pang XY, Krausz KW et al (2013c) Stable isotope- and mass spectrometry-based metabolomics as tools in drug metabolism: a study expanding tempol pharmacology. J Proteome Res 12:1369–1376

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Li F, Patterson AD, Krausz KW et al (2013d) Metabolomics reveals that tumor xenografts induce liver dysfunction. Mol Cell Proteomics 12:2126–2135

    Article  CAS  PubMed  Google Scholar 

  • Li JS, Wang S, Wang MQ, Shi WX, Du XY, Sun CH (2013e) The toxicity of 3-chloropropane-1,2-dipalmitate in Wistar rats and a metabonomics analysis of rat urine by ultra-performance liquid chromatography-mass spectrometry. Chem-Biol Interact 206:337–345

    Article  CAS  PubMed  Google Scholar 

  • Li F, Lu J, Ma XC (2014a) CPY3A4-mediated α-hydroxyaldehyde formation in saquinavir metabolism. Drug Metab Dispos 42:213–220

    Article  CAS  PubMed  Google Scholar 

  • Li M, Li H, Jiang P, Liu X, Xu D, Wang F (2014b) Investigating the pathological processes of rhegmatogenous retinal detachment and proliferative vitreoretinopathy with metabolomics analysis. Mol BioSyst. doi:10.1039/c3mb70386j

    Google Scholar 

  • Liu A, Krausz KW, Fang ZZ, Brocker C, Qu A, Gonzalez FJ (2014) Gemfibrozil disrupts lysophosphatidylcholine and bile acid homeostasis via PPARα and its relevance to hepatotoxicity. Arch Toxicol. doi:10.1007/s00204-013-1188-0

    PubMed Central  Google Scholar 

  • Lu XY, Hu B, Shao L et al (2013) Integrated analysis of transcriptomics and metabonomics profiles in aflatoxin B1-induced hepatotoxicity in rat. Food Chem Toxicol 55:444–455

    Article  CAS  PubMed  Google Scholar 

  • Mahmoudian M, Rahimi-Moghaddam P (2009) The anti-cancer activity of noscapine: a review. Recent Pat Anti-Cancer 4:92–97

    Article  CAS  Google Scholar 

  • Manna SK, Patterson AD, Yang QA et al (2010) Identification of noninvasive biomarkers for alcohol-induced liver disease using urinary metabolomics and the Ppara-null mouse. J Proteome Res 9:4176–4188

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Manna SK, Tanaka N, Krausz KW et al (2014) Biomarkers of coordinate metabolic reprogramming in colorectal tumors in mice and humans. Gastroenterology. doi:10.1053/j.gastro.2014.01.017

    PubMed  Google Scholar 

  • Matsubara T, Tanaka N, Krausz KW et al (2012) Metabolomics identifies an inflammatory cascade involved in dioxin- and diet-induced steatohepatitis. Cell Metab 16(5):634–644

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • McDunn JE, Li Z, Adam KP et al (2013) Metabolomic signatures of aggressive prostate cancer. Prostate 73(14):1547–1560

    Article  CAS  PubMed  Google Scholar 

  • Menezes LF, Zhou F, Patterson AD et al (2012) Network analysis of a Pkd1-mouse model of autosomal dominant polycystic kidney disease identifies HNF4α as a disease Modifier. PLoS Genet 8:e1003053

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Mutlib AE (2008) Application of stable isotope-labeled compounds in metabolism and in metabolism-mediated toxicity studies. Chem Res Toxicol 21:1672–1689

    Article  PubMed  Google Scholar 

  • Patterson AD, Gonzalez FJ, Idle JR (2010) Xenobiotic metabolism: a view through the metabolometer. Chem Res Toxicol 23:851–860

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Patterson AD, Bonzo JA, Li F et al (2011a) Metabolomics reveals attenuation of the SLC6A20 kidney transporter in nonhuman primate and mouse models of type 2 diabetes mellitus. J Biol Chem 286(22):19511–19522

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Patterson AD, Maurhofer O, Beyoglu D et al (2011b) Aberrant lipid metabolism in hepatocellular carcinoma revealed by plasma metabolomics and lipid profiling. Cancer Res 71:6590–6600

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Patterson AD, Shah YM, Matsubara T, Krausz KW, Gonzalez FJ (2012) Peroxisome proliferator-activated receptor α induction of uncoupling protein 2 protects against acetaminophen-induced liver toxicity. Hepatology 56:281–290

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Patterson AD, Carlson BA, Li F et al (2013) Disruption of thioredoxin reductase 1 protects Mice from acute acetaminophen-induced hepatotoxicity through enhanced NRF2 activity. Chem Res Toxicol 26:1088–1096

    Article  CAS  PubMed  Google Scholar 

  • Plumb RS, Stumpf CL, Granger JH, Castro-Perez J, Haselden JN, Dear GJ (2003) Use of liquid chromatography/time-of-flight mass spectrometry and multivariate statistical analysis shows promise for the detection of drug metabolites in biological fluids. Rapid Commun Mass Spectrom 17:2632–2638

    Article  CAS  PubMed  Google Scholar 

  • Qiu YP, Cai GX, Su MM et al (2010) Urinary metabonomic study on colorectal cancer. J Proteome Res 9:1627–1634

    Article  CAS  PubMed  Google Scholar 

  • Rizza S, Copetti M, Rossi C et al (2014) Metabolomics signature improves the prediction of cardiovascular events in elderly subjects. Atherosclerosis 232:260–264

    Article  CAS  PubMed  Google Scholar 

  • Robertson DG (2005) Metabonomics in toxicology: a review. Toxicol Sci 85:809–822

    Article  CAS  PubMed  Google Scholar 

  • Rosenfeldt MT, O’Prey J, Morton JP et al (2013) p53 status determines the role of autophagy in pancreatic tumour development. Nature 504:296–300

    Article  CAS  PubMed  Google Scholar 

  • Schreiber S, Hampe J (2000) Genomics and inflammatory bowel disease. Curr Opin Gastroenterol 16:297–305

    Article  CAS  PubMed  Google Scholar 

  • Schuler M, Muehlbauer P, Guzzie P, Eastmond DA (1999) Noscapine hydrochloride disrupts the mitotic spindle in mammalian cells and induces aneuploidy as well as polyploidy in cultured human lymphocytes. Mutagenesis 14:51–56

    Article  CAS  PubMed  Google Scholar 

  • Shen J, Yan L, Liu S, Ambrosone CB, Zhao H (2013) Plasma metabolomic profiles in breast cancer patients and healthy controls: by race and tumor receptor subtypes. Transl Oncol 6:757–765

    Article  PubMed Central  PubMed  Google Scholar 

  • Shi XL, Yao D, Chen C (2012) Identification of N-acetyltaurine as a novel metabolite of ethanol through metabolomics-guided biochemical analysis. J Biol Chem 287:6336–6349

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Smith KJ, Murray IA, Tanos R et al (2011) Identification of a high-affinity ligand that exhibits complete aryl hydrocarbon receptor antagonism. J Pharmacol Exp Ther 338:318–327

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Suh JH, Kanathezhath B, Shenvi S et al (2014) Thiol/redox metabolomic profiling implicates GSH dysregulation in early experimental graft versus host disease. PLoS ONE 9(2):e88868

    Article  PubMed Central  PubMed  Google Scholar 

  • Tanaka N, Matsubara T, Krausz KW, Patterson AD, Gonzalez FJ (2012) Disruption of phospholipid and bile acid homeostasis in mice with nonalcoholic steatohepatitis. Hepatology 56:118–129

    Article  CAS  PubMed  Google Scholar 

  • Tianjiao L, Shuai W, Xiansheng M et al (2014) Metabolomics coupled with multivariate data and pathway analysis on potential biomarkers in gastric ulcer and intervention effects of Corydalis yanhusuo Alkaloid. PLoS ONE 9:e82499

    Article  PubMed Central  PubMed  Google Scholar 

  • Tsunoda N, Yoshimura H (1981) Metabolic-fate of noscapine 3 further-studies on identification and determination of the metabolites. Xenobiotica 11:23–32

    Article  CAS  PubMed  Google Scholar 

  • Walker GS, Ryder TF, Sharma R, Smith EB, Freund A (2011) Validation of isolated metabolites from drug metabolism studies as analytical standards by quantitative NMR. Drug Metab Dispos 39:433–440

    Article  CAS  PubMed  Google Scholar 

  • Wang TJ, Ngo D, Psychogios N et al (2013) 2-Aminoadipic acid is a biomarker for diabetes risk. J Clin Invest 123:4309–4317

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Xavier RJ, Podolsky DK (2007) Unravelling the pathogenesis of inflammatory bowel disease. Nature 448:427–434

    Article  CAS  PubMed  Google Scholar 

  • Yao D, Shi XL, Wang L, Gosnell BA, Chen C (2013) Characterization of differential cocaine metabolism in mouse and rat through metabolomics-guided metabolite profiling. Drug Metab Dispos 41:79–88

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yin PY, Peter A, Franken H et al (2013) Preanalytical aspects and sample quality assessment in metabolomics studies of human blood. Clin Chem 59:833–845

    Article  CAS  PubMed  Google Scholar 

  • Zhang YY, Li F, Patterson AD et al (2012) Abcb11 deficiency induces cholestasis coupled to impaired β-fatty acid oxidation in mice. J Biol Chem 287:24784–24794

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Zhang N, Seguin RP, Kunze KL, Zhang YY, Jeong H (2013a) Characterization of inhibition kinetics of (S)-warfarin hydroxylation by noscapine: implications in warfarin therapy. Drug Metab Dispos 41:2114–2123

    Article  CAS  PubMed  Google Scholar 

  • Zhang Z, Lu C, Liu X et al (2013b) Global and targeted metabolomics reveal that bupleurotoxin, a toxic type of polyacetylene, induces cerebral lesion by inhibiting GABA receptor in mice. J Proteome Res. doi:10.1021/pr400968c

    Google Scholar 

  • Zhao X, Xu F, Qi B et al (2014) Serum metabolomics study of polycystic ovary syndrome based on liquid chromatography-mass spectrometry. J Proteome Res 13:1101–1111

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported in part by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, and 1R01ES022186-01, National Institutes of Health.

Conflict of interest

The authors have declared that there are no conflicts of interest.

Author information

Authors and Affiliations

  1. Laboratory of Metabolism, Center for Cancer Research, National Institutes of Health, Bethesda, MD, 20892, USA

    Zhong-Ze Fang & Frank J. Gonzalez

Authors
  1. Zhong-Ze Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Frank J. Gonzalez
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Frank J. Gonzalez.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fang, ZZ., Gonzalez, F.J. LC–MS-based metabolomics: an update. Arch Toxicol 88, 1491–1502 (2014). https://doi.org/10.1007/s00204-014-1234-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00204-014-1234-6

Keywords

Search

Navigation