Detection and Structural Characterization of Nucleophiles Trapped Reactive Metabolites of Limonin Using Liquid Chromatography-Mass Spectrometry

Journal of Analytical Methods in Chemistry
Yujie DengQing Yu

Abstract

Limonin (LIM), a furan-containing limonoid, is one of the most abundant components of Dictamnus dasycarpus Turcz. Recent studies demonstrated that LIM has great potential for inhibiting the activity of drug-metabolizing enzymes. However, the mechanisms of LIM-induced enzyme inactivation processes remain unexplored. The main objective of this study was to identify the reactive metabolites of LIM using liquid chromatography-mass spectrometry. Three nucleophiles, glutathione (GSH), N-acetyl cysteine (NAC), and N-acetyl lysine (NAL), were used to trap the reactive metabolites of LIM in in vitro and in vivo models. Two different types of mass spectrometry, a hybrid quadrupole time-of-flight (Q-TOF) mass spectrometry and a LTQ velos Pro ion trap mass spectrometry, were employed to acquire structural information of nucleophile adducts of LIM. In total, six nucleophile adducts of LIM (M1-M6) with their isomers were identified; among them, M1 was a GSH and NAL conjugate of LIM, M2-M4 were glutathione adducts of LIM, M5 was a NAC and NAL conjugate of LIM, and M6 was a NAC adduct of LIM. Additionally, CYP3A4 was found to be the key enzyme responsible for the bioactivation of limonin. This metabolism study largely facilitates the understan...Continue Reading

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Citations

Oct 17, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Shunming FanLingying Yu
Aug 27, 2019·Drug Metabolism Reviews·Bo Wen, Peter Gorycki

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Methods Mentioned

BETA
nuclear magnetic resonance

Software Mentioned

Bruker Daltonics analysis
Xcalibur

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