High-throughput screening for glutathione conjugates using stable-isotope labeling and negative electrospray ionization precursor-ion mass spectrometry

Rapid Communications in Mass Spectrometry : RCM
Shengkai LiaoChristopher L Brummel

Abstract

It has been proposed that the increase in the instances of idiosyncratic adverse drug reactions (IADRs) and black box warnings may be attributed to the occurrence of reactive metabolites. Consequently, a high-throughput screen for reactive metabolites formed from liver microsome extracts with added glutathione (GSH) was developed for use in the early stages of drug discovery. To enhance sensitivity and specificity, as well as accelerate data processing, a mixture of a stable-isotope probe consisting of natural GSH (light GSH) and stable-isotope-labeled [(15) N,(13) C(2)] GSH (heavy GSH) at a ratio of 1:1 was used. Any metabolite that reacted with the GSH results in the formation of light and heavy GSH conjugates with a 3 Da difference. Employing a precursor-ion scan using negative ion electrospray ionization (ESI) corresponding to the expected fragments, signals with the appropriate ratio in the precursor ion scan are then further examined. The new method greatly simplifies data collection by assuming molecules containing GSH will fragment to form specific ions. As such, this approach accelerates data processing (and collection) at the risk of missing compounds that do not fragment as expected. The assay was validated with 33 d...Continue Reading

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Citations

Dec 3, 2014·Journal of Pharmaceutical and Biomedical Analysis·Jan Simon BoermaJan N M Commandeur
Oct 24, 2013·The Plant Journal : for Cell and Molecular Biology·Katharina GläserErwin Grill
Apr 15, 2015·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Nagsen GautamYazen Alnouti
Aug 22, 2012·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Johan BylundTjerk Bueters
Feb 11, 2014·Current Protocols in Toxicology·Robyn L PoerschkeChristopher C Franklin

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