LC-MS-based metabolomics: an update

Abstract

Liquid chromatography-mass spectrometry (LC-MS)-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. This review highlights recent applications of metabolomic technology in the study of xenobiotic metabolism and toxicity, and the understanding of disease pathogenesis and therapeutics. Metabolomics has been employed to study metabolism of noscapine, an aryl hydrocarbon receptor antagonist, and to determine the mechanisms of liver toxicities of rifampicin and isoniazid, trichloroethylene, and gemfibrozil. Metabolomics-based insights into the pathogenesis of inflammatory bowel disease, alcohol-induced liver diseases, non-alcoholic steatohepatitis, and farnesoid X receptor signaling pathway-based therapeutic target discovery will also be discussed. Limitations in metabolomics technology such as sample preparation and lack of LC-MS databases and metabolite standards, need to be resolved in order to improve and broaden the application of metabolomic studies.

Fig. 1

Metabolic mapping of noscapine by use of metabolomics. Novel metabolites discovered by UPLC-ESI-QTOFMS-based metab-olomics (e.g., metabolomics based on ultra-performance liquid chromatography electrospray ionization quadrupole time-of-flight mass spectrometry) are shown by red arrows

Fig. 2

Metabolomics reveals the limitations for the in vivo application of GNF-351 due to poor absorption and high metabolism. The metabolic pathway was determined using UPLC-ESI-QTOFMS-based metabolomics. Red color highlights the drug-metabolizing enzymes regulated by Ahr

Fig. 3

Metabolomics reveals the mechanism of liver toxicity induced by co-therapy with rifampicin and isoniazid. RIF activates human PXR and induction of the PXR target gene Alas leading to increase in protoporphyrin IX (PP-IX) levels. In a mechanism that has yet to be determined, INH could inhibit the downstream enzyme ferroche-latase leading to less heme production and a massive toxic increase in PP-IX

Fig. 4

Major contribution of trichloroacetate (TCA) in trichloroethylene (TCE)-induced biomarkers alteration. TCE can be metabolized to form two PPARα agonists dichloroacetate (DCA) and TCA. The up-regulated expres-sion genes by TCA activation of PPARα results in increased metabolism of fatty acids that results in lower levels of urinary metabolites that reflect fatty acid. TCE-induced hepatomegaly induces altered phospholipid homeostasis in serum

Fig. 5

Metabolomics reveals that PPARα mediated gemfibrozil-induced hepatotoxicity. The therapeutic role of gemfibrozil can be explained by PPARα-induced expression of target genes involved in fatty acid β-oxidation. PPARα-dependent regulation of the metabolic genes involved in the LPC and bile acid metabolism and/or transport result in alteration of downstream metabolic pathways

Fig. 6

Metabolomics reveals the importance of intestinal farnesoid X receptor (FXR) signaling pathway in obesity. Tempol alters the gut microbiome by preferentially killing Lactobacillus and which decreased bile salt hydrolase activity (BSH), which hydrolyzes tauro-β-muricholic acid (TβMCA) that is formed in liver as a result of cholesterol (Chol) metabolism. Lactobacillus BSH efficiently deconju-gates TβMCA to MCA. Lower intestinal Lactobacillus BSH results in increased TβMCA that inhibits intestinal FXR signaling resulting in decreased obesity in high-fat diet-fed mice