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LC-MS/MS Based Detection and Characterization of Covalent Glutathione Modifications Formed by Reactive Drug of Abuse Metabolites

NCJ Number
Date Published
August 2018
1 page
Although tripeptide glutathione (GSH) adducts have been identified for many licit drugs, there is a lack of information on the ability of drugs of abuse to adduct GSH, so the current study used a metabolic assay with GSH as a nucleophilic trapping agent to bind reactive drug metabolites formed in situ.
Conjugation with GSH is a common mechanism of detoxification of many endogenous and exogenous compounds. This phenomenon typically occurs through the formation of a covalent bond between the nucleophilic free thiol moiety of GSH and an electrophilic site on the compound of interest. The current project extracted ion MS spectra were collected via LC-QqQ-MS/MS for all potentially significant ions and examined for fragmentation common to GSH-containing compounds, followed by confirmation of adduction and structural characterization performed by LC-QTOF-MS/MS. In addition to the two positive controls, of the 14 drugs of abuse tested, 10 exhibited GSH adduction, with several forming multiple adducts, resulting in a total of 22 individual identified adducts. A number of these are previously unreported in the literature, including those for diazepam, naltrexone, oxycodone and Δ9-THC. (Publisher abstract modified)

Date Published: August 1, 2018