Review

Targeting human urinary metabolome by LC–MS/MS: a review

Department of Experimental & Health Sciences, Universitat Pompeu Fabra (CEXS-UPF), Doctor Aiguader 88, 08003, Barcelona, Spain

Integrative Pharmacology & Systems Neuroscience Group, IMIM, Hospital del Mar, Doctor Aiguader 88, 08003, Barcelona, Spain

CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN, CB06/03/028), 15706 Santiago de Compostela, Spain

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Óscar J Pozo

*Author for correspondence: Tel.: +34 933 160 472; Fax: +34 933 160 499;

E-mail Address: opozo@imim.es

Integrative Pharmacology & Systems Neuroscience Group, IMIM, Hospital del Mar, Doctor Aiguader 88, 08003, Barcelona, Spain

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Josep Marcos

**Author for correspondence: Tel.: +34 933 160 900; Fax +34 933 160 499;

E-mail Address: josep.marcos@upf.edu

Department of Experimental & Health Sciences, Universitat Pompeu Fabra (CEXS-UPF), Doctor Aiguader 88, 08003, Barcelona, Spain

Cerba Internacional, Pl. Ramon Llull, 7, 08203 Sabadell, Spain

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Published Online:21 Mar 2018https://doi.org/10.4155/bio-2017-0285

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Abstract

Urine is a biological matrix that contains hundreds of metabolic end products which constitute the urinary metabolome. The development and advances on LC–MS/MS have revolutionized the analytical study of biomolecules by enabling their accurate identification and quantification in an unprecedented manner. Nowadays, LC–MS/MS is helping to unveil the complexity of urine metabolome, and the results obtained have multiple biomedical applications. This review focuses on the targeted LC–MS/MS analysis of the urine metabolome. In the first part, we describe general considerations (from sample collection to quantitation) required for a proper targeted metabolic analysis. In the second part, we address the urinary analysis and recent applications of four relevant families: amino acids, catecholamines, lipids and steroids.

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Keywords:

Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

1 Emwas A-HM. The strengths and weaknesses of NMR spectroscopy and mass spectrometry with particular focus on metabolomics research. In: Metabonomics: Methods and Protocols. Bjerrum JT (Ed.). Springer, NY, USA, 161–193 (2015).Crossref, Google Scholar
2 Bouatra S, Aziat F, Mandal R et al. The human urine metabolome. PLoS ONE 8(9), 73076 (2013). •• Extensive analysis of human urine employing six different analytical platforms and covering hundreds of different analytes.Crossref, Medline, CAS, Google Scholar
3 HMDB. www.hmdb.ca.Google Scholar
4 Wishart DS, Feunang YD, Marcu A et al. HMDB 4.0: the human metabolome database for 2018. Nucleic Acids Res. 46(D1), D608–D617 (2018).Crossref, Medline, CAS, Google Scholar
5 Wishart DS. Quantitative metabolomics using NMR. Trends Analyt. Chem. 27(3), 228–237 (2008).Crossref, CAS, Google Scholar
6 Beckonert O, Keun HC, Ebbels TM et al. Metabolic profiling, metabolomic and metabonomic procedures for NMR spectroscopy of urine, plasma, serum and tissue extracts. Nat. Protoc. 2(11), 2692–2703 (2007).Crossref, Medline, CAS, Google Scholar
7 Zhang T, Watson DG. A short review of applications of liquid chromatography mass spectrometry based metabolomics techniques to the analysis of human urine. Analyst 140(9), 2907–2915 (2015). • Short review article focused on recent applications of urinary metabolomic analysis using LC–MS.Crossref, Medline, CAS, Google Scholar
8 Stankovic AK, Dilauri E. Quality improvements in the preanalytical phase: focus on urine specimen workflow. Clin. Lab. Med. 28(2), 339–350 (2008).Crossref, Medline, Google Scholar
9 Ferraz RRN, Baxmann AC, Ferreira LG et al. Preservation of urine samples for metabolic evaluation of stone-forming patients. Urol. Res. 34(5), 329–337 (2006).Crossref, Medline, Google Scholar
10 Delanghe J, Speeckaert M. Preanalytical requirements of urinalysis. Biochem. Medica 24(1), 89–104 (2014).Crossref, Medline, CAS, Google Scholar
11 Marcos J, Pol M, Fabregat A et al. Urinary cysteinyl progestogens: occurrence and origin. J. Steroid Biochem. Mol. Biol. 152(Suppl. C), 53–61 (2015).Crossref, Medline, CAS, Google Scholar
12 Papantoniou K, Pozo OJ, Espinosa A et al. Increased and mistimed sex hormone production in night shift workers. Cancer Epidemiol. Biomarkers Prev. 24(5), 854–863 (2015).Crossref, Medline, CAS, Google Scholar
13 Remer T, Boye KR, Hartmann MF, Wudy SA. Urinary markers of adrenarche: reference values in healthy subjects, aged 3–18 years. J. Clin. Endocrinol. Metab. 90(4), 2015–2021 (2005).Crossref, Medline, CAS, Google Scholar
14 Esko T, Hirschhorn JN, Feldman HA et al. Metabolomic profiles as reliable biomarkers of dietary composition. Am. J. Clin. Nutr. 105(3), 547–554 (2017).Crossref, Medline, CAS, Google Scholar
15 Guasch-Ferré M, Bhupathiraju SN, Hu FB. Use of metabolomics in improving assessment of dietary intake. Clin. Chem. 64(1), 82–98 (2018).Crossref, Medline, CAS, Google Scholar
16 Thompson DK, Sloane R, Bain JR et al. Daily variation of serum acylcarnitines and amino acids. Metabolomics 8(4), 556–565 (2012).Crossref, Medline, CAS, Google Scholar
17 Dunn WB, Broadhurst D, Ellis DI et al. A GC-TOF-MS study of the stability of serum and urine metabolomes during the UK Biobank sample collection and preparation protocols. Int. J. Epidemiol. 37(Suppl. 1), i23–i30 (2008).Crossref, Medline, Google Scholar
18 Laparre J, Kaabia Z, Mooney M et al. Impact of storage conditions on the urinary metabolomics fingerprint. Anal. Chim. Acta 951(Suppl. C), 99–107 (2017).Crossref, Medline, CAS, Google Scholar
19 Tsivou M, Livadara D, Georgakopoulos DG, Koupparis MA, Atta-Politou J, Georgakopoulos CG. Stabilization of human urine doping control samples. Anal. Biochem. 388(2), 179–191 (2009).Crossref, Medline, CAS, Google Scholar
20 Vuckovic D. Current trends and challenges in sample preparation for global metabolomics using liquid chromatography–mass spectrometry. Anal. Bioanal. Chem. 403(6), 1523–1548 (2012).Crossref, Medline, CAS, Google Scholar
21 Deventer K, Pozo OJ, Verstraete AG, Van Eenoo P. Dilute-and-shoot-liquid chromatography-mass spectrometry for urine analysis in doping control and analytical toxicology. Trends Analyt. Chem. 55(Suppl. C), 1–13 (2014).Crossref, CAS, Google Scholar
22 Fernández-Peralbo MA, Luque De Castro MD. Preparation of urine samples prior to targeted or untargeted metabolomics mass-spectrometry analysis. Trends Analyt. Chem. 41(Suppl. C), 75–85 (2012).Crossref, CAS, Google Scholar
23 Pesek JJ, Matyska MT, Loo JA, Fischer SM, Sana TR. Analysis of hydrophilic metabolites in physiological fluids by HPLC–MS using a silica hydride-based stationary phase. J. Sep. Sci. 32(13), 2200–2208 (2009).Crossref, Medline, CAS, Google Scholar
24 Bernini P, Bertini I, Luchinat C, Nincheri P, Staderini S, Turano P. Standard operating procedures for pre-analytical handling of blood and urine for metabolomic studies and biobanks. J. Biomol. NMR 49(3), 231–243 (2011).Crossref, Medline, CAS, Google Scholar
25 Pluym N, Gilch G, Scherer G, Scherer M. Analysis of 18 urinary mercapturic acids by two high-throughput multiplex-LC–MS/MS methods. Anal. Bioanal. Chem. 407(18), 5463–5476 (2015).Crossref, Medline, CAS, Google Scholar
26 Yin S, Su M, Xie G et al. Factors affecting separation and detection of bile acids by liquid chromatography coupled with mass spectrometry in negative mode. Anal. Bioanal. Chem. 409(23), 5533–5545 (2017).Crossref, Medline, CAS, Google Scholar
27 Khamis MM, Adamko DJ, El-Aneed A. Mass spectrometric based approaches in urine metabolomics and biomarker discovery. Mass Spectrom. Rev. 36(2), 115–134 (2017).Crossref, Medline, CAS, Google Scholar
28 Shackleton CH. Profiling steroid hormones and urinary steroids. J. Chromatogr. 379, 91–156 (1986). •• Excellent revision about steroidomics made before metabolomics era.Crossref, Medline, CAS, Google Scholar
29 Vuorensola K, Siren H, Karjalainen U. Determination of dopamine and methoxycatecholamines in patient urine by liquid chromatography with electrochemical detection and by capillary electrophoresis coupled with spectrophotometry and mass spectrometry. J. Chromatogr. B 788(2), 277–289 (2003).Crossref, Medline, CAS, Google Scholar
30 Nováková L, Vlčková H. A review of current trends and advances in modern bio-analytical methods: chromatography and sample preparation. Anal. Chim. Acta 656(1), 8–35 (2009).Crossref, Medline, CAS, Google Scholar
31 Chambers E, Wagrowski-Diehl DM, Lu Z, Mazzeo JR. Systematic and comprehensive strategy for reducing matrix effects in LC/MS/MS analyses. J. Chromatogr. B 852(1–2), 22–34 (2007).Crossref, Medline, CAS, Google Scholar
32 Deng P, Zhan Y, Chen X, Zhong D. Derivatization methods for quantitative bioanalysis by LC–MS/MS. Bioanalysis 4(1), 49–69 (2011).Link, Google Scholar
33 Al Kadhi O, Melchini A, Mithen R, Saha S. Development of a LC–MS/MS method for the simultaneous detection of tricarboxylic acid cycle intermediates in a range of biological matrices. J. Anal. Methods Chem. 2017, 5391832 (2017).Medline, Google Scholar
34 Tan B, Lu Z, Dong S, Zhao G, Kuo MS. Derivatization of the tricarboxylic acid intermediates with O-benzylhydroxylamine for liquid chromatography-tandem mass spectrometry detection. Anal. Biochem. 465, 134–147 (2014).Crossref, Medline, CAS, Google Scholar
35 Chokkathukalam A, Kim D-H, Barrett MP, Breitling R, Creek DJ. Stable isotope-labeling studies in metabolomics: new insights into structure and dynamics of metabolic networks. Bioanalysis 6(4), 511–524 (2014).Link, CAS, Google Scholar
36 Guo K, Li L. Differential 12C-/13C-isotope dansylation labeling and fast liquid chromatography/mass spectrometry for absolute and relative quantification of the metabolome. Anal. Chem. 81(10), 3919–3932 (2009).Crossref, Medline, CAS, Google Scholar
37 Zhou R, Guo K, Li L. 5-Diethylamino-naphthalene-1-sulfonyl Chloride (DensCl): a novel triplex isotope labeling reagent for quantitative metabolome analysis by liquid chromatography mass spectrometry. Anal. Chem. 85(23), 11532–11539 (2013).Crossref, Medline, CAS, Google Scholar
38 Guo K, Li L. High-performance isotope labeling for profiling carboxylic acid-containing metabolites in biofluids by mass spectrometry. Anal. Chem. 82(21), 8789–8793 (2010).Crossref, Medline, CAS, Google Scholar
39 Liu P, Huang YQ, Cai WJ, Yuan BF, Feng YQ. Profiling of thiol-containing compounds by stable isotope labeling double precursor ion scan mass spectrometry. Anal. Chem. 86(19), 9765–9773 (2014).Crossref, Medline, CAS, Google Scholar
40 Tang DQ, Zou L, Yin XX, Ong CN. HILIC-MS for metabolomics: an attractive and complementary approach to RPLC-MS. Mass Spectrom. Rev. 35(5), 574–600 (2016). • Revision of the use of hydrophilic interaction chromatography in metabolomics containing numerous examples of different families of metabolites.Crossref, Medline, CAS, Google Scholar
41 Mcleod MD, Waller CC, Esquivel A et al. Constant ion loss method for the untargeted detection of bis-sulfate metabolites. Anal. Chem. 89(3), 1602–1609 (2017).Crossref, Medline, CAS, Google Scholar
42 Forcisi S, Moritz F, Kanawati B, Tziotis D, Lehmann R, Schmitt-Kopplin P. Liquid chromatography-mass spectrometry in metabolomics research: mass analyzers in ultra high pressure liquid chromatography coupling. J. Chromatogr. A 1292, 51–65 (2013).Crossref, Medline, CAS, Google Scholar
43 An Z, Chen Y, Zhang R et al. Integrated ionization approach for RRLC−MS/MS-based metabonomics: finding potential biomarkers for lung cancer. J. Proteome Res. 9(8), 4071–4081 (2010).Crossref, Medline, CAS, Google Scholar
44 Keski-Hynnilä H, Kurkela M, Elovaara E et al. Comparison of electrospray, atmospheric pressure chemical ionization, and atmospheric pressure photoionization in the identification of apomorphine, dobutamine, and entacapone Phase II metabolites in biological samples. Anal. Chem. 74(14), 3449–3457 (2002).Crossref, Medline, Google Scholar
45 Mcculloch RD, Robb DB. Field-free atmospheric pressure photoionization–liquid chromatography–mass spectrometry for the analysis of steroids within complex biological matrices. Anal. Chem. 89(7), 4169–4176 (2017).Crossref, Medline, CAS, Google Scholar
46 Junot C, Fenaille F, Colsch B, Becher F. High resolution mass spectrometry based techniques at the crossroads of metabolic pathways. Mass Spectrom. Rev. 33(6), 471–500 (2014).Crossref, Medline, CAS, Google Scholar
47 Pozo OJ, Deventer K, Van Eenoo P, Delbeke FT. Presence of endogenous interferences in the urinary detection of selected anabolic steroids by liquid chromatography/electrospray tandem mass spectrometry. Rapid Commun. Mass Spectrom. 21(17), 2785–2796 (2007).Crossref, Medline, CAS, Google Scholar
48 Matuszewski BK, Constanzer ML, Chavez-Eng CM. Matrix effect in quantitative LC/MS/MS analyses of biological fluids: a method for determination of finasteride in human plasma at picogram per milliliter concentrations. Anal. Chem. 70(5), 882–889 (1998).Crossref, Medline, CAS, Google Scholar
49 Stokvis E, Rosing H, Beijnen JH. Stable isotopically labeled internal standards in quantitative bioanalysis using liquid chromatography/mass spectrometry: necessity or not? Rapid Commun. Mass Spectrom. 19(3), 401–407 (2005).Crossref, Medline, CAS, Google Scholar
50 FDA guidelines for Industry. Analytical procedures and methods validation for drugs and biologics. www.fda.gov/downloads/drugs/guidances/ucm386366.pdf.Google Scholar
51 European Medicines Agency. Guideline on Bioanalytical Method Validation. www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2011/08/WC500109686.pdf.Google Scholar
52 Badoud F, Grata E, Boccard J et al. Quantification of glucuronidated and sulfated steroids in human urine by ultra-high pressure liquid chromatography quadrupole time-of-flight mass spectrometry. Anal. Bioanal. Chem. 400(2), 503–516 (2011).Crossref, Medline, CAS, Google Scholar
53 Jemal M, Schuster A, Whigan DB. Liquid chromatography/tandem mass spectrometry methods for quantitation of mevalonic acid in human plasma and urine: method validation, demonstration of using a surrogate analyte, and demonstration of unacceptable matrix effect in spite of use of a stable isotope analog internal standard. Rapid Commun. Mass Spectrom. 17(15), 1723–1734 (2003).Crossref, Medline, CAS, Google Scholar
54 Marcos J, Renau N, Valverde O et al. Targeting tryptophan and tyrosine metabolism by liquid chromatography tandem mass spectrometry. J. Chromatogr. A 1434(Suppl. C), 91–101 (2016).Crossref, Medline, CAS, Google Scholar
55 Warrack BM, Hnatyshyn S, Ott KH et al. Normalization strategies for metabonomic analysis of urine samples. J. Chromatogr. B 877(5–6), 547–552 (2009).Crossref, Medline, CAS, Google Scholar
56 Daskalaki E, Blackburn G, Kalna G, Zhang T, Anthony N, Watson DG. A study of the effects of exercise on the urinary metabolome using normalisation to individual metabolic output. Metabolites 5(1), 119–139 (2015).Crossref, Medline, CAS, Google Scholar
57 Ryan D, Robards K, Prenzler PD, Kendall M. Recent and potential developments in the analysis of urine: a review. Anal. Chim. Acta 684(1–2), 8–20 (2011). •• Summary of many aspects that have to be considered when analyzing urine samples, including a nice description about the challenges of normalization of metabolite concentrations.Crossref, Medline, CAS, Google Scholar
58 Edmands WM, Ferrari P, Scalbert A. Normalization to specific gravity prior to analysis improves information recovery from high resolution mass spectrometry metabolomic profiles of human urine. Anal. Chem. 86(21), 10925–10931 (2014).Crossref, Medline, CAS, Google Scholar
59 Boudonck KJ, Rose DJ, Karoly ED, Lee DP, Lawton KA, Lapinskas PJ. Metabolomics for early detection of drug-induced kidney injury: review of the current status. Bioanalysis 1(9), 1645–1663 (2009).Link, CAS, Google Scholar
60 Ogawa T, Matson WR, Beal MF et al. Kynurenine pathway abnormalities in Parkinson's disease. Neurology 42(9), 1702–1706 (1992).Crossref, Medline, CAS, Google Scholar
61 Palermo M, Shackleton CH, Mantero F, Stewart PM. Urinary free cortisone and the assessment of 11 β-hydroxysteroid dehydrogenase activity in man. Clin. Endocrinol. 45(5), 605–611 (1996).Crossref, Medline, CAS, Google Scholar
62 Shackleton CH, Marcos J, Palomaki GE et al. Dehydrosteroid measurements in maternal urine or serum for the prenatal diagnosis of Smith-Lemli-Opitz syndrome (SLOS). Am. J. Med. Genet. A 143A(18), 2129–2136 (2007).Crossref, Medline, Google Scholar
63 Wu G. Amino acids: metabolism, functions, and nutrition. Amino Acids 37(1), 1–17 (2009).Crossref, Medline, Google Scholar
64 Jones LL, Mcdonald DA, Borum PR. Acylcarnitines: role in brain. Prog. Lipid Res. 49(1), 61–75 (2010).Crossref, Medline, CAS, Google Scholar
65 McGraw-Hill Medical. The online metabolic and molecular bases of inherited disease. https://ommbid.mhmedical.com/book.aspx?bookID=971.Google Scholar
66 Wang TJ, Larson MG, Vasan RS et al. Metabolite profiles and the risk of developing diabetes. Nat. Med. 17(4), 448–453 (2011).Crossref, Medline, Google Scholar
67 Meesters RJW. Bioanalytical LC separation techniques for quantitative analysis of free amino acids in human plasma. Bioanalysis 5(4), 495–512 (2013).Link, CAS, Google Scholar
68 Le A, Ng A, Kwan T, Cusmano-Ozog K, Cowan TM. A rapid, sensitive method for quantitative analysis of underivatized amino acids by liquid chromatography–tandem mass spectrometry (LC–MS/MS). J. Chromatogr. B 944(Suppl. C), 166–174 (2014).Crossref, Medline, CAS, Google Scholar
69 National Metabolic Biochemistry Network. www.metbio.net/metbioguidelines.asp.Google Scholar
70 Kaspar H, Dettmer K, Chan Q et al. Urinary amino acid analysis: a comparison of iTRAQ^®–LC–MS/MS, GC–MS, and amino acid analyzer. J. Chromatogr. B 877(20), 1838–1846 (2009).Crossref, Medline, CAS, Google Scholar
71 Rotter M, Brandmaier S, Prehn C et al. Stability of targeted metabolite profiles of urine samples under different storage conditions. Metabolomics 13(1), 4 (2017). • Detailed study about the influence of storage condition on the urinary metabolome, with special emphasis in amino acids.Crossref, Medline, Google Scholar
72 Gray N, Plumb R. A validated method for the quantification of amino acids in mammalian urine. Waters Corporation Application note 2016. www.waters.com.Google Scholar
73 Qu J, Wang Y, Luo G, Wu Z, Yang C. Validated quantitation of underivatized amino acids in human blood samples by volatile ion-pair reversed-phase liquid chromatography coupled to isotope dilution tandem mass spectrometry. Anal. Chem. 74(9), 2034–2040 (2002).Crossref, Medline, CAS, Google Scholar
74 Waterval WAH, Scheijen JLJM, Ortmans-Ploemen MMJC, Habets-Van Der Poel CD, Bierau J. Quantitative UPLC–MS/MS analysis of underivatised amino acids in body fluids is a reliable tool for the diagnosis and follow-up of patients with inborn errors of metabolism. Clin. Chim. Acta 407(1), 36–42 (2009).Crossref, Medline, CAS, Google Scholar
75 Imtakt. Intrada amino acids separation column for LC–MS. www.imtaktusa.com.Google Scholar
76 Schooneman MG, Vaz FM, Houten SM, Soeters MR. Acylcarnitines. Diabetes 62(1), 1–8 (2013).Crossref, Medline, CAS, Google Scholar
77 Minkler PE, Stoll MSK, Ingalls ST, Kerner J, Hoppel CL. Validated method for the quantification of free and total carnitine, butyrobetaine, and acylcarnitines in biological samples. Anal. Chem. 87(17), 8994–9001 (2015).Crossref, Medline, CAS, Google Scholar
78 Minkler PE, Stoll MSK, Ingalls ST, Kerner J, Hoppel CL. Quantitative acylcarnitine determination by UHPLC–MS/MS – going beyond tandem MS acylcarnitine ‘profiles’. Mol. Gen. Metab. 116(4), 231–241 (2015).Crossref, Medline, CAS, Google Scholar
79 Minkler PE, Stoll MSK, Ingalls ST, Hoppel CL. Selective and accurate C5 acylcarnitine quantitation by UHPLC–MS/MS: distinguishing true isovaleric acidemia from pivalate derived interference. J. Chromatogr. B 1061–1062(Suppl. C), 128–133 (2017).Crossref, Medline, CAS, Google Scholar
80 Bassi R, Niewczas MA, Biancone L et al. Metabolomic profiling in individuals with a failing kidney allograft. PLoS ONE 12(1), e0169077 (2017).Crossref, Medline, Google Scholar
81 Dong S, Zhan Z-Y, Cao H-Y et al. Urinary metabolomics analysis identifies key biomarkers of different stages of nonalcoholic fatty liver disease. World J. Gastroenterol. 23(15), 2771–2784 (2017).Crossref, Medline, CAS, Google Scholar
82 Fang L, Gu C, Liu X et al. Metabolomics study on primary dysmenorrhea patients during the luteal regression stage based on ultra performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry. Mol. Med. Rep. 15(3), 1043–1050 (2017).Crossref, Medline, CAS, Google Scholar
83 Abe K, Suzuki H, Maekawa M, Shimada M, Yamaguchi H, Mano N. Matrix effect–corrected liquid chromatography/tandem mass-spectrometric method for determining acylcarnitines in human urine. Clin. Chim. Acta 468(Suppl. C), 187–194 (2017).Crossref, Medline, CAS, Google Scholar
84 Li X, Li S, Kellermann G. Pre-analytical and analytical validations and clinical applications of a miniaturized, simple and cost-effective solid phase extraction combined with LC–MS/MS for the simultaneous determination of catecholamines and metanephrines in spot urine samples. Talanta 159(Suppl. C), 238–247 (2016).Crossref, Medline, CAS, Google Scholar
85 Boomsma F, Alberts G, Van Eijk L, Man in 't Veld AJ, Schalekamp MA. Optimal collection and storage conditions for catecholamine measurements in human plasma and urine. Clin. Chem. 39(12), 2503–2508 (1993).Crossref, Medline, CAS, Google Scholar
86 Peitzsch M, Pelzel D, Lattke P, Siegert G, Eisenhofer G. Preservation of urine free catecholamines and their free O-methylated metabolites with citric acid as an alternative to hydrochloric acid for LC–MS/MS-based analyses. Clin. Chem. Lab. Med. 54(1), 37 (2016).Crossref, Medline, CAS, Google Scholar
87 Bergmann ML, Sadjadi S, Schmedes A. Analysis of catecholamines in urine by unique LC/MS suitable ion-pairing chromatography. J. Chromatogr. B 1057(Suppl. C), 118–123 (2017).Crossref, Medline, CAS, Google Scholar
88 Shen Y, Cheng L, Guan Q, Li H, Lu J, Wang X. Development and validation of a liquid chromatography tandem mass spectrometry method for the measurement of urinary catecholamines in diagnosis of pheochromocytoma. Biomed. Chromatogr. 31(11), e4003–e4003 (2017).Crossref, Google Scholar
89 Woo HI, Yang JS, Oh HJ et al. A simple and rapid analytical method based on solid-phase extraction and liquid chromatography–tandem mass spectrometry for the simultaneous determination of free catecholamines and metanephrines in urine and its application to routine clinical analysis. Clin. Biochem. 49(7), 573–579 (2016).Crossref, Medline, CAS, Google Scholar
90 Diniz MER, Vilhena LS, Paulo BP, Barbosa TCC, Mateo EC. Simultaneous determination of catecholamines and metanephrines in urine by liquid chromatography electrospray ionization tandem mass spectrometry: successful clinical application. J. Braz. Chem. Soc. 26, 1684–1691 (2015).CAS, Google Scholar
91 Gabler J, Wang S. Quantification of metanephrine and normetanephrine in urine using liquid chromatography-tandem mass spectrometry. In: Clinical Applications of Mass Spectrometry in Biomolecular Analysis: Methods and Protocols. Garg U (Ed.). Springer, NY, USA, 149–157 (2016).Crossref, Google Scholar
92 Li X, Li S, Wynveen P, Mork K, Kellermann G. Development and validation of a specific and sensitive LC–MS/MS method for quantification of urinary catecholamines and application in biological variation studies. Anal. Bioanal. Chem. 406(28), 7287–7297 (2014).Crossref, Medline, CAS, Google Scholar
93 Konieczna L, Roszkowska A, Niedźwiecki M, Bączek T. Hydrophilic interaction chromatography combined with dispersive liquid–liquid microextraction as a preconcentration tool for the simultaneous determination of the panel of underivatized neurotransmitters in human urine samples. J. Chromatogr. A 1431(Suppl. C), 111–121 (2016).Crossref, Medline, CAS, Google Scholar
94 Ghosh A, Nishtala K. Biofluid lipidome: a source for potential diagnostic biomarkers. Clin. Transl. Med. 6, 22 (2017).Crossref, Medline, Google Scholar
95 Graessler J, Mehnert CS, Schulte KM et al. Urinary Lipidomics: evidence for multiple sources and sexual dimorphism in healthy individuals. Pharmacogenomics J. doi:10.1038/tpj.2017.24 (2017) (Epub ahead of print).Crossref, Medline, Google Scholar
96 Bligh EG, Dyer WJ. A rapid method of total lipid extraction and purification. Can. J. Biochem. Physiol. 37(8), 911–917 (1959).Crossref, Medline, CAS, Google Scholar
97 Folch J, Lees M, Stanley GHS. A simple method for the isolation and purification of total lipides from animal tissues. J. Biol. Chem. 226(1), 497–509 (1957).Crossref, Medline, CAS, Google Scholar
98 Matyash V, Liebisch G, Kurzchalia TV, Shevchenko A, Schwudke D. Lipid extraction by methyl-tert-butyl ether for high-throughput lipidomics. J. Lip. Res. 49(5), 1137–1146 (2008).Crossref, Medline, CAS, Google Scholar
99 Tipthara P, Thongboonkerd V. Differential human urinary lipid profiles using various lipid-extraction protocols: MALDI-TOF and LIFT-TOF/TOF analyses. Sci. Rep. 6, 33756 (2016).Crossref, Medline, CAS, Google Scholar
100 Breitkopf SB, Ricoult SJH, Yuan M et al. A relative quantitative positive/negative ion switching method for untargeted lipidomics via high resolution LC–MS/MS from any biological source. Metabolomics 13(3), 30 (2017).Crossref, Medline, Google Scholar
101 Byeon SK, Lee JY, Lee J-S, Moon MH. Lipidomic profiling of plasma and urine from patients with Gaucher disease during enzyme replacement therapy by nanoflow liquid chromatography–tandem mass spectrometry. J. Chromatogr. A 1381(Suppl. C), 132–139 (2015).Crossref, Medline, CAS, Google Scholar
102 Gorden DL, Myers DS, Ivanova PT et al. Biomarkers of NAFLD progression: a lipidomics approach to an epidemic. J. Lip. Res. 56(3), 722–736 (2015). •• Nice example of a combination of differently targeted lipidomic analyses in several matrices (liver, plasma and urine) with a potential application to the diagnostics of nonalcoholic fatty liver disease.Crossref, Medline, CAS, Google Scholar
103 Rockwell HE, Gao F, Chen EY et al. Dynamic assessment of functional lipidomic analysis in human urine. Lipids 51(7), 875–886 (2016).Crossref, Medline, CAS, Google Scholar
104 Cho K, Moon JS, Kang JH et al. Combined untargeted and targeted metabolomic profiling reveals urinary biomarkers for discriminating obese from normal-weight adolescents. Pediatr. Obes. 12(2), 93–101 (2017).Crossref, Medline, CAS, Google Scholar
105 Fu J, Schoeman JC, Harms AC et al. Metabolomics profiling of the free and total oxidised lipids in urine by LC–MS/MS: application in patients with rheumatoid arthritis. Anal. Bioanal. Chem. 408(23), 6307–6319 (2016).Crossref, Medline, CAS, Google Scholar
106 Wang M, Wang C, Han RH, Han X. Novel advances in shotgun lipidomics for biology and medicine. Prog. Lipid Res. 61, 83–108 (2016).Crossref, Medline, CAS, Google Scholar
107 Zhao Y-Y, Vaziri ND, Lin R-C. Chapter six – lipidomics: new insight into kidney disease. In: Advances in Clinical Chemistry. Makowski GS (Ed.). Elsevier, Amsterdam, The Netherlands, 153–175 (2015).Google Scholar
108 Ovčačíková M, Lísa M, Cífková E, Holčapek M. Retention behavior of lipids in reversed-phase ultrahigh-performance liquid chromatography–electrospray ionization mass spectrometry. J. Chromatogr. A 1450(Suppl. C), 76–85 (2016).Crossref, Medline, CAS, Google Scholar
109 Lueke AJ, Meeusen JW, Donato LJ, Gray AV, Butterfield JH, Saenger AK. Analytical and clinical validation of an LC–MS/MS method for urine leukotriene E4: a marker of systemic mastocytosis. Clin. Biochem. 49(13), 979–982 (2016).Crossref, Medline, CAS, Google Scholar
110 Xiao Y, Fu X, Pattengale P, Dien Bard J, Xu Y-K, O'Gorman MR. A sensitive LC–MS/MS method for the quantification of urinary 8-iso-prostaglandin F2α (8-iso-PGF2α) including pediatric reference interval. Clin. Chim. Acta 460(Suppl. C), 128–134 (2016).Crossref, Medline, CAS, Google Scholar
111 Peng M, Liu L, Jiang M et al. Measurement of free carnitine and acylcarnitines in plasma by HILIC-ESI-MS/MS without derivatization. J. Chromatogr. B 932(Suppl. C), 12–18 (2013).Crossref, Medline, CAS, Google Scholar
112 Koivusalo M, Haimi P, Heikinheimo L, Kostiainen R, Somerharju P. Quantitative determination of phospholipid compositions by ESI-MS: effects of acyl chain length, unsaturation, and lipid concentration on instrument response. J. Lip. Res. 42(4), 663–672 (2001).Crossref, Medline, Google Scholar
113 Biocrates. List of isobaric and isomeric lipids. www.biocrates.com/images/List-of-Isobaric-and-Isomeric-Lipid-Species.pdf.Google Scholar
114 Yang K, Han X. Lipidomics: techniques, applications, and outcomes related to biomedical sciences. Trends Biochem. Sci. 41(11), 954–969 (2016).Crossref, Medline, CAS, Google Scholar
115 Okemoto K, Maekawa K, Tajima Y, Tohkin M, Saito Y. Cross-classification of human urinary lipidome by sex, age, and body mass index. PLoS ONE 11(12), e0168188 (2016).Crossref, Medline, Google Scholar
116 Jeanneret F, Tonoli D, Rossier MF, Saugy M, Boccard J, Rudaz S. Evaluation of steroidomics by liquid chromatography hyphenated to mass spectrometry as a powerful analytical strategy for measuring human steroid perturbations. J. Chromatogr. A 1430, 97–112 (2016).Crossref, Medline, CAS, Google Scholar
117 Sjovall J. Fifty years with bile acids and steroids in health and disease. Lipids 39(8), 703–722 (2004). • Nice historic perspective about steroid measurements in health and disease.Crossref, Medline, Google Scholar
118 Homer N, Kothiya S, Rutter A, Walker BR, Andrew R. Gas chromatography tandem mass spectrometry offers advantages for urinary steroids analysis. Anal. Biochem. 538, 34–37 (2017).Crossref, Medline, CAS, Google Scholar
119 Catlin DH, Sekera MH, Ahrens BD, Starcevic B, Chang YC, Hatton CK. Tetrahydrogestrinone: discovery, synthesis, and detection in urine. Rapid Commun. Mass Spectrom. 18(12), 1245–1249 (2004).Crossref, Medline, CAS, Google Scholar
120 Gomez C, Fabregat A, Pozo ÓJ, Marcos J, Segura J, Ventura R. Analytical strategies based on mass spectrometric techniques for the study of steroid metabolism. Trends Analyt. Chem. 53(Suppl. C), 106–116 (2014).Crossref, CAS, Google Scholar
121 Penning TM, Lee S-H, Jin Y, Gutierrez A, Blair IA. Liquid-chromatography mass spectrometry (LC–MS) of steroid hormone metabolites and its applications. J. Steroid Biochem. Mol. Biol. 121(3–5), 546–555 (2010).Crossref, Medline, CAS, Google Scholar
122 Jerjes WK, Cleare AJ, Peters TJ, Taylor NF. Circadian rhythm of urinary steroid metabolites. Ann. Clin. Biochem. 43(Pt 4), 287–294 (2006).Crossref, Medline, CAS, Google Scholar
123 Pozo OJ, Marcos J, Fabregat A et al. Adrenal hormonal imbalance in acute intermittent porphyria patients: results of a case control study. Orphanet J. Rare Dis. 9, 54– (2014).Crossref, Medline, Google Scholar
124 De La Torre R, De La Torre X, AlíA C, Segura J, Baró T, Torres-RodríGuez JM. Changes in androgenic steroid profile due to urine contamination by microorganisms: a prospective study in the context of doping control. Anal. Biochem. 289(2), 116–123 (2001).Crossref, Medline, CAS, Google Scholar
125 Tsivou M, Livadara D, Georgakopoulos DG, Koupparis MA, Atta-Politou J, Georgakopoulos CG. Stabilization of human urine doping control samples: II. microbial degradation of steroids. Anal. Biochem. 388(1), 146–154 (2009).Crossref, Medline, CAS, Google Scholar
126 Tsivou M, Giannadaki E, Hooghe F et al. Doping control container for urine stabilization: a pilot study. Drug Test. Anal. 9(5), 699–712 (2017).Crossref, Medline, CAS, Google Scholar
127 Schanzer W, Opfermann G, Donike M. 17-Epimerization of 17 α-methyl anabolic steroids in humans: metabolism and synthesis of 17 α-hydroxy-17 β-methyl steroids. Steroids 57(11), 537–550 (1992).Crossref, Medline, CAS, Google Scholar
128 Fabregat A, Marcos J, Segura J, Ventura R, Pozo OJ. Factors affecting urinary excretion of testosterone metabolites conjugated with cysteine. Drug Test. Anal. 8(1), 110–119 (2016).Crossref, Medline, Google Scholar
129 Schanzer W. Metabolism of anabolic androgenic steroids. Clin. Chem. 42(7), 1001–1020 (1996).Crossref, Medline, CAS, Google Scholar
130 Meng LJ, Griffiths WJ, Sjovall J. The identification of novel steroid N-acetylglucosaminides in the urine of pregnant women. J. Steroid Biochem. Mol. Biol. 58(5–6), 585–598 (1996).Crossref, Medline, CAS, Google Scholar
131 Hofmann AF. The continuing importance of bile acids in liver and intestinal disease. Arch. Intern. Med. 159(22), 2647–2658 (1999).Crossref, Medline, CAS, Google Scholar
132 O'byrne J, Hunt MC, Rai DK, Saeki M, Alexson SEH. The human bile acid-CoA:amino acid N-acyltransferase functions in the conjugation of fatty acids to glycine. J. Biol. Chem. 278(36), 34237–34244 (2003).Crossref, Medline, Google Scholar
133 Krone N, Hughes BA, Lavery GG, Stewart PM, Arlt W, Shackleton CHL. Gas chromatography/mass spectrometry (GC/MS) remains a pre-eminent discovery tool in clinical steroid investigations even in the era of fast liquid chromatography tandem mass spectrometry (LC/MS/MS). J. Steroid Biochem. Mol. Biol. 121(3–5), 496–504 (2010).Crossref, Medline, CAS, Google Scholar
134 Mareck U, Geyer H, Opfermann G, Thevis M, Schänzer W. Factors influencing the steroid profile in doping control analysis. J. Mass Spectrom. 43(7), 877–891 (2008).Crossref, Medline, CAS, Google Scholar
135 Fabregat A, Pozo OJ, Marcos J, Segura J, Ventura R. Use of LC–MS/MS for the open detection of steroid metabolites conjugated with glucuronic acid. Anal. Chem. 85(10), 5005–5014 (2013).Crossref, Medline, CAS, Google Scholar
136 Stevenson BJ, Waller CC, Ma P et al. Pseudomonas aeruginosa arylsulfatase: a purified enzyme for the mild hydrolysis of steroid sulfates. Drug Test. Anal. 7(10), 903–911 (2015).Crossref, Medline, CAS, Google Scholar
137 Athanasiadou I. Chemical derivatization to enhance ionization of anabolic steroids in LC–MS for doping-control analysis. Trends Analyt. Chem. 42, 137–156 (2013).Crossref, CAS, Google Scholar
138 Higashi T, Shimada K. Derivatization of neutral steroids to enhance their detection characteristics in liquid chromatography–mass spectrometry. Anal. Bioanal. Chem. 378(4), 875–882 (2004).Crossref, Medline, CAS, Google Scholar
139 Marcos J, Pozo OJ. Derivatization of steroids in biological samples for GC–MS and LC–MS analyses. Bioanalysis 7(19), 2515–2536 (2015).Link, CAS, Google Scholar
140 Strahm E, Kohler I, Rudaz S et al. Isolation and quantification by high-performance liquid chromatography–ion-trap mass spectrometry of androgen sulfoconjugates in human urine. J. Chromatogr. A 1196–1197(Suppl. C), 153–160 (2008).Crossref, Medline, CAS, Google Scholar
141 Jänne O, Vihko R, Sjövall J, Sjövall K. Determination of steroid mono- and disulfates in human plasma. Clin. Chim. Acta 23(3), 405–412 (1969).Crossref, Medline, CAS, Google Scholar
142 Mckinney AR, Cawley AT, Young EB et al. The metabolism of anabolic-androgenic steroids in the greyhound. Bioanalysis 5(7), 769–781 (2013).Link, CAS, Google Scholar
143 Marcos J, Pozo OJ. Current LC–MS methods and procedures applied to the identification of new steroid metabolites. J. Steroid Biochem. Mol. Biol. 162(Suppl. C), 41–56 (2016).Crossref, Medline, CAS, Google Scholar
144 Marcos J, Renau N, Casals G, Segura J, Ventura R, Pozo OJ. Investigation of endogenous corticosteroids profiles in human urine based on liquid chromatography tandem mass spectrometry. Anal. Chim. Acta 812(Suppl. C), 92–104 (2014).Crossref, Medline, CAS, Google Scholar
145 Pozo OJ, Van Eenoo P, Deventer K, Delbeke FT. Ionization of anabolic steroids by adduct formation in liquid chromatography electrospray mass spectrometry. J. Mass Spectrom. 42(4), 497–516 (2007).Crossref, Medline, CAS, Google Scholar
146 Rannulu NS, Cole RB. Novel fragmentation pathways of anionic adducts of steroids formed by electrospray anion attachment involving regioselective attachment, regiospecific decompositions, charge-induced pathways, and ion–dipole complex intermediates. J. Am. Soc. Mass. Spectrom. 23(9), 1558–1568 (2012).Crossref, Medline, CAS, Google Scholar
147 Pozo OJ, Van Eenoo P, Van Thuyne W, Deventer K, Delbeke FT. Direct quantification of steroid glucuronides in human urine by liquid chromatography-electrospray tandem mass spectrometry. J. Chromatogr. A 1183(1–2), 108–118 (2008).Crossref, Medline, CAS, Google Scholar
148 Badoud F, Boccard J, Schweizer C, Pralong F, Saugy M, Baume N. Profiling of steroid metabolites after transdermal and oral administration of testosterone by ultra-high pressure liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. J. Steroid Biochem. Mol. Biol. 138(Suppl. C), 222–235 (2013).Crossref, Medline, CAS, Google Scholar
149 Boccard J, Badoud F, Jan N et al. Untargeted profiling of urinary steroid metabolites after testosterone ingestion: opening new perspectives for antidoping testing. Bioanalysis 6(19), 2523–2536 (2014).Link, CAS, Google Scholar
150 Palermo A, Botre F, De La Torre X, Zamboni N. Non-targeted LC–MS based metabolomics analysis of the urinary steroidal profile. Anal. Chim. Acta 964, 112–122 (2017).Crossref, Medline, CAS, Google Scholar
151 Hintikka L, Kuuranne T, Aitio O, Thevis M, Schanzer W, Kostiainen R. Enzyme-assisted synthesis and structure characterization of glucuronide conjugates of eleven anabolic steroid metabolites. Steroids 73(3), 257–265 (2008).Crossref, Medline, CAS, Google Scholar
152 Jantti SE, Kiriazis A, Reinila RR, Kostiainen RK, Ketola RA. Enzyme-assisted synthesis and characterization of glucuronide conjugates of neuroactive steroids. Steroids 72(3), 287–296 (2007).Crossref, Medline, Google Scholar
153 Chetwynd AJ, Samarawickrama A, Vera JH et al. Nanoflow-nanospray mass spectrometry metabolomics reveals disruption of the urinary metabolite profiles of HIV-positive patients on combination antiretroviral therapy. J. Acquir. Immune Defic. Syndr. 74(2), e45–e53 (2017).Crossref, Medline, CAS, Google Scholar
154 Liang Q, Liu H, Xie L-X, Li X, Zhang A-H. High-throughput metabolomics enables biomarker discovery in prostate cancer. RSC Adv. 7(5), 2587–2593 (2017).Crossref, CAS, Google Scholar
155 Boelaert J, Lynen F, Glorieux G, Schepers E, Neirynck N, Vanholder R. Metabolic profiling of human plasma and urine in chronic kidney disease by hydrophilic interaction liquid chromatography coupled with time-of-flight mass spectrometry: a pilot study. Anal. Bioanal. Chem. 409(8), 2201–2211 (2017).Crossref, Medline, CAS, Google Scholar
156 Luan H, Liu L-F, Meng N et al. LC–MS-based urinary metabolite signatures in idiopathic Parkinson's disease. J. Proteome Res. 14(1), 467–478 (2015).Crossref, Medline, CAS, Google Scholar
157 Jeanneret F, Boccard J, Badoud F et al. Human urinary biomarkers of dioxin exposure: analysis by metabolomics and biologically driven data dimensionality reduction. Toxicol. Lett. 230(2), 234–243 (2014).Crossref, Medline, CAS, Google Scholar
158 Singh GK, Balzer BW, Kelly PJ et al. Urinary sex steroids and anthropometric markers of puberty – a novel approach to characterising within-person changes of puberty hormones. PLoS ONE 10(11), e0143555 (2015).Crossref, Medline, Google Scholar
159 Bufa A, Farkas N, Preisz Z et al. Diagnostic relevance of urinary steroid profiles on ovarian granulosa cell tumors: two case reports. J. Med. Case Rep. 11(1), 166 (2017).Crossref, Medline, Google Scholar
160 Kamrath C, Wettstaedt L, Boettcher C, Hartmann MF, Wudy SA. The urinary steroidome of treated children with classic 21-hydroxylase deficiency. J. Steroid. Biochem. Mol. Biol. 165(Pt B), 396–406 (2017).Crossref, Medline, CAS, Google Scholar
161 Velikanova LI, Shafigullina ZR, Lisitsin AA et al. Different types of urinary steroid profiling obtained by high-performance liquid chromatography and gas chromatography-mass spectrometry in patients with adrenocortical carcinoma. Horm. Cancer 7(5–6), 327–335 (2016).Crossref, Medline, CAS, Google Scholar
162 Torchen LC, Idkowiak J, Fogel NR et al. Evidence for increased 5-α-reductase activity during early childhood in daughters of women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 101(5), 2069–2075 (2016).Crossref, Medline, CAS, Google Scholar
163 Demetrowitsch TJ, Petersen B, Keppler JK et al. Validation of a two-step quality control approach for a large-scale human urine metabolomic study conducted in seven experimental batches with LC/QTOF-MS. Bioanalysis 7(1), 103–112 (2015).Link, CAS, Google Scholar
164 Chen Y, Xu J, Zhang R, Abliz Z. Methods used to increase the comprehensive coverage of urinary and plasma metabolomes by MS. Bioanalysis 8(9), 981–997 (2016).Link, CAS, Google Scholar
165 García A, Godzien J, López-Gonzálvez Á, Barbas C. Capillary electrophoresis mass spectrometry as a tool for untargeted metabolomics. Bioanalysis 9(1), 99–130 (2016).Link, Google Scholar
166 Gowda GAN, Djukovic D. Overview of mass spectrometry-based metabolomics: opportunities and challenges. Methods Mol. Biol. 1198, 3–12 (2014).Crossref, Medline, CAS, Google Scholar
167 Paglia G, Astarita G. Metabolomics and lipidomics using traveling-wave ion mobility mass spectrometry. Nat. Protoc. 12, 797 (2017).Crossref, Medline, CAS, Google Scholar
168 Zhang X, Quinn K, Cruickshank-Quinn C, Reisdorph R, Reisdorph N. The application of ion mobility mass spectrometry to metabolomics. Curr. Opin. Chem. Biol. 42(Suppl. C), 60–66 (2018).Crossref, Medline, CAS, Google Scholar

Vol. 10, No. 7

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Received 20 December 2017

Accepted 30 January 2018

Published online 21 March 2018

Published in print April 2018

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Financial & competing interests disclosure

J Rodríguez-Morató acknowledges funding from the EU's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No 712949 (TECNIOspring PLUS) and from the Agency for Business Competitiveness of the Government of Catalonia. Spanish Health National System is acknowledged for O J Pozo contract (CPII16/00027). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

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