LC-MS-Based Metabolomics in Drug Metabolism

Chen, Chi; Gonzalez, Frank J.; Idle, Jeffrey R.

doi:10.1080/03602530701497804

Cited by 239 publications

(161 citation statements)

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“…Therefore, effective methods for prioritizing, studying, and ultimately identifying uncharacterized metabolites is a critical development for LC/MS based metabolomics [5][6][7][8][9][10]. Here we discuss current LC/MS metabolomic approaches (detailed elsewhere [2,4,11,12]) and their integration into 'Metabolite Atlases' to facilitate annotation and prioritization of uncharacterized metabolites. …”

mentioning

confidence: 99%

Dealing with the unknown: Metabolomics and Metabolite Atlases

Bowen

Northen

2010

J. Am. Soc. Mass Spectrom.

178

158

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Metabolomics is the comprehensive profiling of the small molecule composition of a biological sample. Since metabolites are often the indirect products of gene expression, this approach is being used to provide new insights into a variety of biological systems (clinical, bioenergy, etc.). A grand challenge for metabolomics is the complexity of the data, which often include many experimental artifacts. This is compounded by the tremendous chemical diversity of metabolites. Identification of each uncharacterized metabolite is in many ways its own puzzle (compared with proteomics, which is based on predictable fragmentation patterns of polypeptides). Therefore, effective data reduction/prioritization strategies are critical for this rapidly developing field. Here we review liquid chromatography electrospray ionization mass spectrometry (LC/MS)-based metabolomics, methods for feature finding/prioritization, approaches for identifying unknown metabolites, and construction of method specific 'Metabolite Atlases'.(J Am Soc Mass Spectrom 2010, 21, 1471-1476) © 2010 Published by Elsevier Inc. on behalf of American Society for Mass Spectrometry N ature utilizes a tremendous diversity of metabolites, and it is estimated that there are Ͼ200,000 plant metabolites alone [1]. Metabolomics is a rapidly growing field for studying the small molecule composition of a biological system. Liquid chromatography coupled to electrospray ionization mass spectrometry (LC/MS) is becoming a method of choice for profiling metabolites in complex biological samples. This is due to its ability to effectively ionize a breath of metabolites with minimal fragmentation (versus gas chromatography-mass spectroscopy (GC/MS), robustness, and ability to scale-up to support tandem mass spectrometry based structural studies (versus capillary electrophoresis-mass spectrometry (CE-MS)) [2]. However, known metabolites are typically a small portion of the data obtained in a LC/MS metabolomics experiment (ϳ10%) [3] where the bulk are MS-artifacts and uncharacterized metabolites.Identification of unknown metabolites is cost and effort intensive, often requiring preparative scale isolation for nuclear magnetic resonance (NMR) studies or extensive chemical synthesis to enable structural comparisons using tandem mass spectrometry (MS/MS) [4]. Therefore, it is not surprising that the majority of reports focus on changes in metabolites that have authentic standards or at a minimum are found in metabolite databases. Yet, there are only a few thousand commercially available analytical standards due to lack of demand and the inherent instability of many metabolites. These standards and the endogenous metabolites contained in databases represent only a portion of endogenous metabolites. Therefore, effective methods for prioritizing, studying, and ultimately identifying uncharacterized metabolites is a critical development for LC/MS based metabolomics [5][6][7][8][9][10]. Here we discuss current LC/MS metabolomic approaches (detailed elsewhere [2,4,11,12]) and their inte...

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mentioning

confidence: 99%

Dealing with the unknown: Metabolomics and Metabolite Atlases

Bowen

Northen

2010

J. Am. Soc. Mass Spectrom.

178

158

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“…Moreover, metabolomics, a tool for measuring small-molecule metabolite profiles and fluxes in biological matrices (Chen et al, 2007), was used to monitor the effect of hPXR activation and CYP3A4 induction on APAP metabolism. The data revealed that hPXR activation and CYP3A4 induction enhanced APAP-induced liver injury.…”

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confidence: 99%

Rifampicin-Activated Human Pregnane X Receptor and CYP3A4 Induction Enhance Acetaminophen-Induced Toxicity

Cheng¹,

Ma²,

Krausz³

et al. 2009

Drug Metab Dispos

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ABSTRACT:Acetaminophen (APAP) is safe at therapeutic levels but causes hepatotoxicity via N-acetyl-p-benzoquinone imine-induced oxidative stress upon overdose. To determine the effect of human (h) pregnane X receptor (PXR) activation and CYP3A4 induction on APAP-induced hepatotoxicity, mice humanized for PXR and CYP3A4 (TgCYP3A4/hPXR) were treated with APAP and rifampicin. Human PXR activation and CYP3A4 induction enhanced APAPinduced hepatotoxicity as revealed by hepatic alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities elevated in serum, and hepatic necrosis after coadministration of rifampicin and APAP, compared with APAP administration alone. In contrast, hPXR mice, wild-type mice, and Pxr-null mice exhibited significantly lower ALT/AST levels compared with TgCYP3A4/ hPXR mice after APAP administration. Toxicity was coincident with depletion of hepatic glutathione and increased production of hydrogen peroxide, suggesting increased oxidative stress upon hPXR activation. Moreover, mRNA analysis demonstrated that CYP3A4 and other PXR target genes were significantly induced by rifampicin treatment. Urinary metabolomic analysis indicated that cysteine-APAP and its metabolite S-(5-acetylamino-2-hydroxyphenyl)mercaptopyruvic acid were the major contributors to the toxic phenotype. Quantification of plasma APAP metabolites indicated that the APAP dimer formed coincident with increased oxidative stress. In addition, serum metabolomics revealed reduction of lysophosphatidylcholine in the APAP-treated groups. These findings demonstrated that human PXR is involved in regulation of APAP-induced toxicity through CYP3A4-mediated hepatic metabolism of APAP in the presence of PXR ligands.

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“…To achieve that, IPF is a stable isotope-based metabolomics approach using compound labeled with 2 H, 13 C, 15 N, or 18 O that can be used to facilitate identi cation of the metabolites. 42,48,49) e stable isotope ratio (1 : 1) from spiked native and isotope-labeled compounds were used for metabolite signal detection.…”

Section: Methods Of Mass Spectrometry In Dis-covery Of Exposure Markermentioning

confidence: 99%

Exposure Marker Discovery of Phthalates Using Mass Spectrometry

2017

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Phthalates are chemicals widely used in industry and the consequences on human health caused by exposure to these agents are of signi cant interest currently. e urinary metabolites of phthalates can be measured and used as exposure markers for the assessment of the actual internal contamination of phthalates coming from di erent sources and absorbed by various ways. e purpose of this paper is to review the markers for exposure and risk assessment of phthalates such as di-methyl phthalate (DMP), di-ethyl phthalate (DEP), di-butyl phthalate (DBP), benzylbutyl phthalate (BBP), di-(2-ethylhexyl)phthalate (DEHP), di-(2-propylheptyl)phthalate (DPHP), di-iso-nonyl phthalate (DINP), di-n-octyl phthalate (DnOP) and di-isodecyl phthalate (DIDP), and introduction of the analytical approach of three metabolomics data processing approaches that can be used for chemical exposure marker discovery in urine with high-resolution mass spectrometry (HRMS) data.

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LC-MS-Based Metabolomics in Drug Metabolism

Cited by 239 publications

References 50 publications

Dealing with the unknown: Metabolomics and Metabolite Atlases

Dealing with the unknown: Metabolomics and Metabolite Atlases

Rifampicin-Activated Human Pregnane X Receptor and CYP3A4 Induction Enhance Acetaminophen-Induced Toxicity

Exposure Marker Discovery of Phthalates Using Mass Spectrometry

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