Lc-ms-based metabolomics in drug metabolism pdf

Lcmsbased metabolomic approach is promising for the quality control of dietary supplements and discovery of novel markers in biomedical research. Metabolomicsanalytical methods wikibooks, open books. Metabolomicsanalytical methodsmass spectrometrylcms. A metabolomics cellbased approach for anticipating and. Lcmsbased metabolomics molecular biosystems rsc publishing. Perturbations in cardiac energy metabolism are major contributors to a number of cardiovascular pathologies. Lcmsbased metabolomics of xenobioticinduced toxicities. The success of a lcmsbased metabolomic study often depends on multiple experimental, analytical, and computational steps. The workflow and utility of different analytical platforms to profile complex biological matrices that include biofluids, brain tissue and cells, are shown in. Xenobiotic metabolism, a ubiquitous natural response to foreign compounds, elicits initiating signals for many. Metabolomics and human nutrition british journal of.

However, no holistic metabolic information of curcumin on hyperlipidemia models has been revealed, which may provide us an insight into the underlying mechanism. Therefore, this technique has been used widely for disease diagnostic biomarker discovery jansson et al. Through metabolomics viral infections are not canonically considered metabolic diseases. Abstractsince metabolism significantly affects drug safety and efficacy, determining the metabolic profile of a drug is a critical part of drug development. The application of an lcmsbased metabolomic approach has gained more widespread use in identifying drug metabolites, developing metabolic maps and lending clues to mechanisms of bioactivation. In this study, cocaine metabolism in the mouse and rat was characterized through lc ms based metabolomic analysis of urine samples and were further compared through calculating the relative abundance of individual cocaine metabolites. This article explores applicable approaches using lc ms based metabolomic techniques to facilitate problems in drug metabolism. Using metabolomics to investigate biomarkers of drug. The emerging role of metabolomics in the diagnosis and. The focus of this report concerns the use of nuclear magnetic resonance nmr spectroscopy for metabolic analyses and, in particular, its use in toxicology for examining. Department of systems biology, technical university of denmark. Unlike gc ms, there are no spectral libraries for lc ms compound identification. In the present work, the potential and challenges of an integrated strategy based on lcswathms for simultaneous drug metabolism and metabolomics studies was investigated. Lcmsbased metabolomics in the study of druginduced.

In addition, comorbidities associated with cardiovascular disease cvd can alter systemic and myocardial metabolism, often contributing to the worsening of cardiac function and health outcomes. Liquid chromatography lc in combination with tandem mass spectrometry ms ms offers a robust, reliable, and economical methodology for quantitative single metabolite analysis and profiling of complete metabolite classes of a biological specimen over a. Nov 24, 2017 in summary, the data obtained through lc ms based global metabolomics, targeted metabolomics and kinetic isotope analysis indicated that slc25a22 knockdown inhibited the biosynthesis of aspderived amino acids and polyamines in krasmutant crc cells. The analysis of metabolites in human body fluids remains a challenge because of their chemical diversity and dynamic concentration range. Metformin was detected in ah of people taking this drug. Furthermore, the addition of polyamine into culture medium can modulate crc cell growth. Therefore, there is an increased demand for global metabolomics methods to provide. Lcmsbased metabolomics has being widely used in traditional chinese medicines tcms research due to the great coverage of mass ranges, high sensitivity to detect metabolites, and no need of sample derivatization. Sequential window acquisition of all theoretical fragmention spectra swath has recently emerged as a powerful high resolution mass spectrometric data independent acquisition technique. Stateoftheart metabolomic technologies give us the ability to measure thousands of. Lcmsbased metabolomics workflow and research applications.

In summary, the data obtained through lcmsbased global metabolomics, targeted metabolomics and kinetic isotope analysis indicated that slc25a22 knockdown inhibited the biosynthesis of aspderived amino acids and polyamines in krasmutant crc cells. Metabolic characterisation of thp1 macrophage polarisation. Metabolites observed are dependent upon the concentration found in the sample but a general outline of metabolites are found below. Apr 08, 2014 liquid chromatographymass spectrometry lcms 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. Liquid chromatography lc in combination with tandem mass spectrometry msms offers a robust, reliable, and economical methodology for quantitative single metabolite analysis and profiling of complete metabolite classes of a biological specimen over a. Recently, his group has been developing and characterizing p450 and xenobiotic receptor humanized mice and has combined these and other gene knockout models with the use of lcmsbased metabolomics to study xenobiotic metabolism and to develop biomarkers for p450 expression and receptor activation. Untargeted metabolomics offers the potential to discover modes of action for drugs that perturb cellular metabolism. Lcms metabolomics analysis thermo fisher scientific us. Within drug discovery and development there is an increased reliance on metabolic biomarkers to monitor disease, establish phenotypic screens, understand mechanisms of action for active compounds, and monitor in vivo and clinical studies. Lcmsbased metabolomics in understanding the mechanisms. This article explores applicable approaches using lcms based metabolomic techniques to facilitate problems in drug metabolism. Investigators compared the in vitro and in vivo methods in drug metabolism to lcms techniques and showed that lcms has an advantage because of its capacity to hold large datasets and is able to graphically represent. Development of high resolution lcms methods and improved data analysis software now allows rapid detection of druginduced changes to cellular metabolism in.

Metabolomics aims at identification and quantitation of small molecules involved in metabolic reactions. Gonzalez from national cancer institute at the national institute of health expanded lcmsbased metabolomics for xenobiotic metabolism studies by developing various strategies, including 1 identification of metabolites by metabolomic analysis with or without xenobiotic intervention figure 1, and, 2 validation of. By comparison to traditional in vitro and in vivo methods in drug metabolism, lcmsbased metabolomics techniques show clear advantages in the capacity of handling large datasets and in the graphical representation of metabolismrelated sample classification, as well as in the indiscriminative nature of metabolite identification. Lc ms based metabolomics has being widely used in traditional chinese medicines tcms research due to the great coverage of mass ranges, high sensitivity to detect metabolites, and no need of sample derivatization. Unlike gcms, there are no spectral libraries for lcms compound identification. Through its ability to provide information on changes in multiple metabolic pathways with changes in levels of large number of individual metabolites, metabolomics offers a. A metabolomics cellbased approach for anticipating and investigating druginduced liver injury. The application of an lcmsbased metabolomic approach has gained more widespread use in identifying drug metabolites, developing metabolic maps and lending clues to mechanisms of. Although nmrbased metabolomics has been widely used in metabolomic studies, msbased metabolomics is increasingly employed because of its high resolution and sensitivity as well as the more wide availability of instruments. In the present work, nmr and ms based metabolomics was conducted to investigate the intervention effect of curcumin on. By comparison to traditional in vitro and in vivo methods in drug metabolism, lc ms based metabolomics techniques show clear advantages in the capacity of handling large datasets and in the graphical representation of metabolism related sample classification, as well as in the indiscriminative nature of metabolite identification. Abstractsimilar to genomics and proteomics which yield vast amounts of data about the expression of genes and proteins, metabolomics refers to the whole metabolic profile of the cell. Liquid chromatographymass spectrometry lcms 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. Besides lipids, chemicalinduced changes in amino acid metabolism, antioxidant turnover, and carbohydrate metabolism, have also been effectively examined by lcmsbased metabolomics 6264.

Special issue metabolomics and microbiota metabolism. Representative raw chromatograms produced by lcmsbased metabolomics. Applications of lc ms based metabolomics in exploratory and hypothesisdriven investigations of xit are illustrated by case studies of xenobiotic metabolism and endogenous metabolism associated with xenobiotic exposure. Stable isotope and mass spectrometrybased metabolomics as.

Abstract liquid chromatographymass spectrometry lcms based metabolomics has been facilitated by the construction of ms 2 spectral tag ms2t library from the total scan esi msms data, and the development of widely targeted metabolomics method using msms data gathered from authentic standards. Thus, the lcmsbased metabolomic approach is a powerful tool for profiling of drug metabolism and bioactivation. An lcmsbased metabolomic strategy for studying drug metabolism although nmrbased metabolomics has been widely used in metabolomic studies, msbased metabolomics is increasingly employed because of its high resolution and sensitivity as well as the more wide availability of instruments. Investigators compared the in vitro and in vivo methods in drug metabolism to lc ms techniques and showed that lc ms has an advantage because of its capacity to hold large datasets and is able to graphically represent.

Ms based metabonomic approaches just fit the purpose. Lcmsbased metabolomics has a great potential in drug metabolism, identification of biomarkers of cause andor effect, and revealing the novel mechanisms of drug toxicity. Metabolomics is the investigation of metabolites in any sample type and finds application in diverse areas including biomarker discovery, systems biology, and drug discovery. The role of metabolomics in brain metabolism research. Lcms based metabolomics magdenoska, olivera publication date. A metabolomics cell based approach for anticipating and investigating drug induced liver injury. However, the causes behind this speciesdependent sensitivity to cocaine have not been elucidated. Lcmsbased metabolomics in profiling of drug metabolism. The application of mass spectrometrybased metabolomics in the field of drug metabolism has yielded important insights not only into the metabolic routes of drugs but has provided unbiased, global perspectives of the endogenous metabolome that can be useful for identifying biomarkers associated with mechanism of action, efficacy, and toxicity. Metabolomics reveals the novel mechanism of drug toxicity feng li university of kansas medical center, usa abstract druginduced toxicity is a big issue in the clinical practice. Dandan hu, xinglong chen, xuerong xiao, yikun wang, fang liu, qi zhao, xian li, xiuwei yang, fei li. Lcmsbased metabolomics in understanding the mechanisms of. Lc ms based metabolomics of xenobioticinduced toxicities.

Specific urine metabolites as early predictors of druginduced liver injury j. Biomarker discovery for cytochrome p450 1a2 activity assessment in rats, based on metabolomics xiao pu 1,2, yiqiao gao 1,2, ruiting li 1,2, wei li 1,2, yuan tian 1,2, zunjian zhang 1,2, and fengguo xu 1,2, 1 key laboratory of drug quality control and pharmacovigilance ministry of education. Stable isotope and mass spectrometrybased metabolomics. Most drugs may cause adverse drug reactions, in small portion of patients. Within drug discovery and development there is an increased reliance on metabolic biomarkers to. Identification of metabolites, data standardization, export and finding a biomarker is a real challenge 0 300 500 700 900 1100 0 1500 1700 mz 100 % mass spectrometry in quantitative. Here, we have implemented an lcmsbased method that allows large scale quanti. The application of mass spectrometry based metabolomics in the field of drug metabolism has yielded important insights not only into the metabolic routes of drugs but has provided unbiased, global perspectives of the endogenous metabolome that can be useful for identifying biomarkers associated with mechanism of action, efficacy, and toxicity.

Lc ms has enjoyed a growing popularity as the platform for metabolomic studies due to its high throughput, soft ionization, and good coverage of metabolites. Lcms has enjoyed a growing popularity as the platform for metabolomic studies due to its high throughput, soft ionization, and good coverage of metabolites. To our knowledge, this is the first metabolomics study aiming to assess differences in ah composition between diabetic and non. The focus of this report concerns the use of nuclear magnetic resonance nmr spectroscopy for metabolic analyses and, in particular, its use in toxicology for examining the metabolic profile of biofluids.

Dec 15, 2014 lcms based metabolites workflow and research applications by emily humphreys 12. Drug addiction has been associated with an increased risk for cancer, psychological complications, heart, liver, and lung disease, as well as infection. Metabolomics is a field where the discovery of specific cellular metabolites is essential to the field. Application of novel systems biology techniques, such as metabolomics, that allow surveillance of changes in multiple cellular pathways could significantly improve our ability to monitor disease development. Metabolite identification and quantitation in lcmsmsbased metabolomics. Biomarker discovery for cytochrome p450 1a2 activity. Within the past decade, it has become evident that microbiota produce a plethora of metabolites that can profoundly affect the human host by impacting physiology and. Gonzalez from national cancer institute at the national institute of health expanded lc ms based metabolomics for xenobiotic metabolism studies by developing various strategies, including 1 identification of metabolites by metabolomic analysis with or without xenobiotic intervention figure 1, and, 2 validation of. Although nmrbased metabolomics has been widely used in metabolomic studies, msbased metabolomics is increasingly employed because of its high resolution and sensitivity as. Jul 27, 2016 pharmacokinetics and metabolism of vincamine and related compounds.

Xenobiotic metabolism, a ubiquitous natural response to foreign compounds, elicits initiating signals for many pathophysiological events. A metabolite extract was analyzed by lchighresolution ms in negative ion mode on a standalone orbitrap instrument. Characterization of differential cocaine metabolism in mouse. Applications of lcmsbased metabolomics in exploratory and hypothesisdriven investigations of xit are illustrated by case studies of xenobiotic metabolism and endogenous metabolism associated with xenobiotic exposure. However, because the precursor or molecular ion is usually present with lcms, it is a crucial part of the metabolite identification strategy and is used to search databases of metabolites, such as the metlin database and mzcloud online fragmentation library. Lcmsbased metabolomics in profiling of drug metabolism and. As a significant component of biological system, gut flora preform metabolic reactions that differ from their host, producing both nutrients and non. Lcms based metabolites workflow and research applications by emily humphreys 12. Metabolomics reveals the novel mechanism of drug toxicity. Without the tools and methods to discover the metabolites, metabolite profiles and cellular processes unique to organisms cannot be discovered. Swath acquisition mode for drug metabolism and metabolomics. The topics covered include a metabolomic field overview and the challenges in neuroscience metabolomics. With the recent advances in high resolution accurate.

Currently, most widely used techniques for identifying xenobiotic metabolites and metabolic pathways are empirical and largely based on in vitro incubation assays and in vivo radiotracing experiments. Metabolomics enables the comprehensive profiling of cellular metabolites at the systems level, thereby providing a direct readout of biochemical activity that can be correlated with phenotype and. Metabolomics and human nutrition volume 105 issue 8 sandy primrose, john draper, rachel elsom, verity kirkpatrick, john c. Understand the mechanism could help us to predict, prevent, and treat the druginduced toxicity. Optimisation of these models requires quantitative information, including metabolite concentrations andor metabolic. Lcmsbased metabolomics in the study of druginduced liver injury. Ms based pharmacokinetic, metabolic, and phytochemical metabolomic studies of ginseng, and metabonomic. Liquid chromatographymass spectrometry lcmsbased 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.

Curcumin, a principle bioactive component of curcuma longa l, is well known for its antihyperlipidemia effect. However, because the precursor or molecular ion is usually present with lc ms, it is a crucial part of the metabolite identification strategy and is used to search databases of metabolites, such as the metlin database and mzcloud online fragmentation library. An lcmsbased metabolomic strategy for studying drug metabolism. While genes have been identified that can mark individuals at risk for substance abuse, the initiation step of addiction is attributed to persistent metabolic disruptions occurring following the first instance of narcotic drug use. Similar to genomics and proteomics which yield vast amounts of data about the expression of genes and proteins, metabolomics refers to the whole metabolic profile of the cell. Lcmsbased metabolomics in traditional chinese medicines. A comparison of a typical protocol for xenobiotic intervention studies using lcmsbased metabolomics andtheclassicallcmsbasedwork owisillustratedin figure. In the future, metabolomics integrating with other omics can serve as an effective tool for investigating the mechanisms of drug toxicity.

Lc ms based metabolomics in understanding the mechanisms of alzheimers disease and biomarker discovery. Mar 22, 2012 metabolomics enables the comprehensive profiling of cellular metabolites at the systems level, thereby providing a direct readout of biochemical activity that can be correlated with phenotype and. Development of high resolution lc ms methods and improved data analysis software now allows rapid detection of drug induced changes to cellular metabolism in an untargeted manner. An increased oxidative stress and perturbations in amino acid metabolism in ah may be responsible for earlier cataract onset in diabetic patients. Lcmsbased metabolomics revealed slc25a22 as an essential. Mathers, chris seal, manfred beckmann, sumanto haldar, john h. Stateoftheart metabolomic technologies give us the ability to measure thousands. In addition, lcmsbased approach has been employed to investigate the function of immune cells and immune responses by monitoring level changes of signalling molecules. A novel integrated method for largescale detection.