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© Borgis - Postępy Nauk Medycznych 6/2018, s. 366-369 | DOI: 10.25121/PNM.2018.31.6.366
*Damian Gorczyca, Elzbieta Makomaska-Szaroszyk, Lukasz Szarpak, Kacper Kranc
Mass spectrometry as a potential technique for clinical medicine
Spektrometria mas jako potencjalna technika w medycynie klinicznej
Lazarski University, Warsaw, Poland
Streszczenie
Metabolomika, proteomika i genomika cieszą się zainteresowaniem naukowców, w tym również z dziedziny nauk medycznych. Odkrycie nowych leków, ich metabolitów, sposobu ich działania, metabolizmu czy ostatecznie ich wchłaniania w organizmie mają bezpośrednie przełożenie w leczeniu chorób. Odkrycie nowych szlaków metabolicznych zaangażowanych w procesy chorobotwórcze może prowadzić do lepszego zrozumienia zjawisk na poziomie komórkowym. Sekwencjonowanie genomu, poznanie jego struktury czy jego wpływu na kodowanie białek to nowe dziedziny, które dostarczają informacji na temat przebiegu procesów biochemicznych i metabolicznych, w tym wielu chorób. Metabolomika pozwala na pozyskanie informacji na temat procesów wewnątrzkomórkowych, badanie wpływu środków farmakologicznych na organizm, na identyfikację nowych, nieznanych szlaków metabolicznych biorących udział w procesach chorobotwórczych, monitorowanie znanych chorób metabolicznych czy badanie farmakokinetyki nowych leków. Poznanie całego metabolomu człowieka to ogromne wyzwanie dla nauk medycznych. Ciężko jest poznać metabolom prostych organizmów. Kluczowe dane, czyli mechanizmy działania organizmu, procesy biochemiczne, etiologia chorób nadal pozostają nierozwikłane, dlatego też metabolomika jako dziedzina będzie się wciąż rozwijała. Proteomika jest skomplikowaną i wymagającą dziedziną badań. Związane jest to z dynamicznym i niejednorodnym charakterem proteomu oraz jego zmiennym. Białka jako podstawowy budulec żywych organizmów pełnią jednocześnie szereg ról w procesach biochemicznych. Poznanie procesów u zdrowego człowieka jest wyzwaniem dla proteomiki, a tym bardziej poznanie procesów biologicznych w stanie patologii jest szczególnie ważne i również kluczowe dla tej dziedziny nauki. Poza metabolomiką i proteomiką pozostają jeszcze klasyczne, ale również istotne badania z zakresu toksykologii, medycyny sądowej czy badania farmakokinetyczne. Ten rodzaj badań jest najbardziej powszechny, gdzie wykorzystuje się spektrometrię mas jako podstawowe narzędzie analityczne.
Summary
Metabolomics, proteomics and genomics are popular with scientists, including those in the field of medical science. The discovery of new drugs of their metabolites, their mode of action, metabolism or eventually their absorption in the body have a direct impact in the treatment of diseases. The discovery of new metabolic pathways involved in pathogenic processes may lead to a better understanding of phenomena at the cellular level. Genome sequencing, understanding its structure and its impact on protein coding are new areas that provide information on the course of biochemical and metabolic processes, including many diseases. Metabolomics allows to obtain information about intracellular processes, study of the influence of pharmacological agents on the body, identification of new, unknown metabolic pathways involved in pathogenic processes, monitoring of known metabolic diseases or pharmacokinetic study of new drugs. The task of knowing the entire human metabolome is a huge challenge for medical sciences. It is difficult to know the metabolisms of simple organisms. Key data, mechanisms of the body's activity, biochemical processes, etiology of diseases are still not unraveled, therefore metabolomics as a field will continue to develop. Proteomics is a complicated and demanding field of research. This is related to the dynamic and heterogeneous character of the proteome and its variable. Proteins as the basic building block of living organisms play simultaneously a series of roles in biochemical processes. Understanding processes in a healthy human is a challenge for proteomics, and the more the recognition of biological processes in the state of pathology is particularly important and also crucial for this field of science. In addition to metabolomics and proteomics, classical, but also significant, toxicology, forensic, or pharmacokinetic studies remain. This type of research is the most common, where mass spectrometry is used as the basic analytical tool.
INTRODUCTION
In the last decade, omics techniques (i.e. genomics, metabolomics and proteomics) have commonly entered the world of science as a field of key importance for humans and the environment. Along with the development of knowledge about the information contained in the genetic material, the emphasis was placed on the search for markers in physiological disorders. The markers can be small molecular compounds (metabolomics) or proteins (proteomics). In particular, proteomics is currently the direction of research by doctors, geneticists, biotechnologists and chemists. Compared to genomics that only studies the sequence of genes, proteomics allows us to track changes in protein activity as post-translational modifications (PTMs). In addition to proteins, small-molecule compounds that perform important functions in the body (e.g. inhibitors of biochemical transformations) remain to be tested. Therefore, the second area that is also important for science is metabolomics. The results of metabolic testing give information about the mechanisms already taking place at the cellular level. Studying metabolomics allows us to obtain information about intracellular processes, study the influence of pharmacological agents on the body, identify new and unknown metabolic pathways involved in pathogenic processes, and monitor known metabolic diseases or pharmacokinetic study of new drugs. Proteomics is a complex and demanding field of research. This is related to the dynamic and heterogeneous character of the proteome and its variable and often low concentration (pmol/ml). The technique that found application in mass genomics, proteomics and metabolomics is mass spectrometry. Mass spectrometry is a widely used measuring technique in many medical, natural and exact sciences. It is used for quantitative and qualitative determination of chemical compounds and elements and their isotopes. Obtained mass spectrum provides a lot of information about the composition of the sample, and in many cases, clearly identifies the components of the mixture, in particular biological ones, where the matrix’s influence on the obtained result is observed. Although this method is constantly updated, nevertheless, thanks to its advantages, it is considered an extremely important measurement tool. In practice, it is possible to use different measuring systems, selected depending on the type of sample and the type of information sought. In each case, however, several basic components of the measurement system are distinguished.
Sample preparation, in particular if it is a biological material (i.e. organs, cerebrospinal fluid, cell cultures, saliva, blood or urine) is the key to correct determinations of a selected group of compounds. In areas of science such as medicine, access to biological material that is the subject of the analysis is limited, therefore each quantity is valuable. In addition, it should be remembered that the acquisition of material is associated with the disruption of tissue continuity. Therefore, the consent of the appropriate bioethics committee and the consent of the examined person is required (as in this case). It is imperative to be especially careful when collecting biological material, working with it and disposing of residues. The result of the analysis depends on the type of biological material and its preparation. Therefore, an appropriate method of sample preparation should be chosen for the determination of a selected group of compounds (proteins or small molecule compounds < 2000 Da). The method of collecting biological material and its storage has a key impact on the results of analyses. From the moment of collection, the material should be stored at low temperatures, depending on the chemical nature of the material being tested and the schedule of planned analyses. It is important that the biological material is not thawed several times, because the whole structure and the number of analytes determined may change, which will ultimately affect the test result. This would have an effect on obtaining false positives and/or false negative results.
REVIEW
The attention of scientists for a long time is focused on standard qualitative research and quantitative biological material (e.g. urine, blood, serum, plasma, hair, cerebrospinal fluid) focusing on the search for disease markers and metabolism studies (1, 2). Thanks to its very good sensitivity and selectivity, mass spectrometry is considered a great achievement of modern technology.
The term metabolomics, defining a comprehensive analysis of small molecules involved in the metabolic pathways of living organisms, was coined by Oliver Fiehn in 2002. The first group of compounds on which the analysis of mass spectrometry is worth attention are anabolic-androgenic steroids (SAA). Quantitative determination of selected SAAs is carried out routinely using the enzyme immunoassay method (due to the speed of analysis and its price), however, in order to fully confirm the quantitative steroid profile, the GC-MS or GC-MS/MS technique is used (fig. 1a, b). These techniques are particularly important in the study of congenital adrenal hyperplasia in children, where a steroid profile, consisting of about 40 different steroids, is formed, and the presence of each steroid is associated with the activity of a specific enzyme (e.g. 21-hydroxylase, 3β-hydroxysteroid dehydrogenase – type 2, 17α-hydroxylase) in the steroidogenesis pathway. Methodology for the preparation of urine samples for the determination of SAA, in which hydrolysis, solid-phase extraction (SPE) is used, and ultimately the derivation of salicylate derivatives (TMS) is a well-known diagnostic laboratory. Thanks to studies on the metabolism of anabolic-androgenic steroids in children with congenital diseases, effective treatment of patients with accurate diagnosis can be undertaken (3, 4).
Fig. 1a, b. Example (A) chromatogram (GC-MS) and (B) MS spectrum in SCAN mode for androsterone, bis-TMS and etiocholonolone, bis-TMS

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Piśmiennictwo
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2. Näsström E, Jonsson P, Johansson A et al.: Diagnostic metabolite biomarkers of chronic typhoid carriage. PLoS Negl Trop Dis 2018; 12(1): e0006215.
3. Handelsman DJ, Wartofsky L: Requirement for mass spectrometry sex steroid assays in the Journal of Clinical Endocrinology and Metabolism. J Clin Endocrinol Metab 2013; 98(10): 3971-3973.
4. El-Farhan N, Rees DA, Evans C: Measuring cortisol in serum, urine and saliva – are our assays good enough? Ann Clin Biochem 2017; 54(3): 308-322.
5. Bärebring L, Bullarbo M, Glantz A et al.: Trajectory of vitamin D status during pregnancy in relation to neonatal birth size and fetal survival: a prospective cohort study. BMC Pregnancy Childbirth 2018; 18(1): 51.
6. Sharer JD, De Biase I, Matern D et al.; ACMG Laboratory Quality Assurance Committee: Laboratory analysis of amino acids, 2018 revision: a technical standard of the American College of Medical Genetics and Genomics (ACMG). Genet Med 2018; 20(12): 1499-1507.
7. Mussap M, Zaffanello M, Fanos V: Metabolomics: a challenge for detecting and monitoring inborn errors of metabolism. Ann Transl Med 2018; 6(17): 338.
8. Schulze A, Lindner M, Kohlmüller D et al.: Expanded newborn screening for inborn errors of metabolism by electrospray ionization-tandem mass spectrometry: results, outcome, and implications. Pediatrics 2003; 111(6 Pt 1): 1399-1406.
9. Wang L, Tang Z, Shi M et al.: Pharmacokinetic study of sirolimus ophthalmic formulations by consecutive sampling and liquid chromatography-tandem mass spectrometry. J Pharm Biomed Anal 2019; 164: 337-344.
10. Iwamoto N, Yokoyama K, Takanashi M et al.: Application of nSMOL coupled with LC-MS bioanalysis for monitoring the Fc-fusion biopharmaceuticals Etanercept and Abatacept in human serum. Pharmacol Res Perspect 2018; 6(4): e00422.
11. Reusch D, Haberger M, Falck D et al.: Comparison of methods for the analysis of therapeutic immunoglobulin G Fc-glycosylation profiles. Part 2: Mass spectrometric methods. MAbs 2015; 7(4): 732-742.
12. Houde D, Engen JR: Conformational analysis of recombinant monoclonal antibodies with hydrogen/deuterium exchange mass spectrometry. Methods Mol Biol 2013; 988: 269-289.
otrzymano: 2018-11-12
zaakceptowano do druku: 2018-12-03

Adres do korespondencji:
*Damian Gorczyca
Lazarski University
43 Swieradowska Str., 02-662 Warsaw, Poland
Phone: (+48) 604989358
E-mail: damian.gorczyca@lazarski.pl

Postępy Nauk Medycznych 6/2018
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