Lc-MS-Based Metabolomics of Xenobiotic-Induced Toxicities

Abstract

Xenobiotic exposure, especially high-dose or repeated exposure of xenobiotics, can elicit detrimental effects on biological systems through diverse mechanisms. Changes in metabolic systems, including formation of reactive metabolites and disruption of endogenous metabolism, are not only the common consequences of toxic xenobiotic exposure, but in many cases are the major causes behind development of xenobiotic-induced toxicities (XIT). Therefore, examining the metabolic events associated with XIT generates mechanistic insights into the initiation and progression of XIT, and provides guidance for prevention and treatment. Traditional bioanalytical platforms that target only a few suspected metabolites are capable of validating the expected outcomes of xenobiotic exposure. However, these approaches lack the capacity to define global changes and to identify unexpected events in the metabolic system. Recent developments in high-throughput metabolomics have dramatically expanded the scope and potential of metabolite analysis. Among all analytical techniques adopted for metabolomics, liquid chromatography-mass spectrometry (LC-MS) has been most widely used for metabolomic investigations of XIT due to its versatility and sensitivity in metabolite analysis. In this review, technical platform of LC-MS-based metabolomics, including experimental model, sample preparation, instrumentation, and data analysis, are discussed. Applications of LC-MS-based metabolomics in exploratory and hypothesis-driven investigations of XIT are illustrated by case studies of xenobiotic metabolism and endogenous metabolism associated with xenobiotic exposure.

Revisiting the Metabolism and Bioactivation of Ketoconazole in Human and Mouse Using Liquid Chromatography–Mass Spectrometry-Based Metabolomics

“…Therefore, the results were strongly empirical and dependent on the investigator’s level of knowledge. However, metabolomics-guided drug metabolism studies have not focused on specific metabolic pathways; therefore, this non-targeted approach facilitates the identification of novel metabolites, the characterization of metabolic enzymes, and the profiling of reactive metabolites [32,36,37,38,39,40,41,42]. This approach is complementary to conventional drug metabolism studies.…”

“…Overall strategies were adapted from previous reports [39,40,46]. Orbitrap™ MS spectral data were pre-processed with MZmine 2 (available on: , version 2.20) [47], which was used to detect mass spectra, build and deconvolute chromatograms, remove isotopes, align chromatograms, and generate a data matrix of ion identity ( m / z and retention time) with abundance.…”

Metabolomic analysis to define and compare the effects of PAHs and oxygenated PAHs in developing zebrafish

“…This latter approach allows graphical depiction of any significant differences in the patterns, which often provides information about toxicity mechanisms, pathways and possible biomarkers of exposure (Dumas et al, 2014; Prosser et al, 2014). Among the analytical instrumentations most commonly used for metabolomics studies, liquid chromatography-mass spectrometry (LC-MS) provides a powerful platform for the identification of metabolites indicative of biological and environmental perturbations (Zhou et al, 2012; Chen and Kim, 2013). Moreover, the power of the LC-MS-based metabolomics can be amplified when coupled with genomics approaches as a means to link genetic variants to phenotypic traits (Suhre and Gieger, 2012; Adamski and Suhre, 2013).…”

Concurrent profiling of polar metabolites and lipids in human plasma using HILIC-FTMS

“…Blood samples are relatively easy to collect, less invasive and more stable, compared to other body fluids. Therefore, metabolite profiling of blood samples has been widely used in biomarker discovery67891011 and assessments of adverse outcome pathways (AOPs) induced by chemicals12, drugs131415 and environmental stress16. Liquid chromatography coupled with mass spectrometry (LC-MS) is one of the main techniques for blood plasma metabolite profiling171819.…”