Glutathione conjugates of the mercapturic acid pathway and guanine adduct as biomarkers of exposure to CEES, a sulfur mustard analog
- 7 January 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Analytical and Bioanalytical Chemistry
- Vol. 413 (5), 1337-1351
- https://doi.org/10.1007/s00216-020-03096-4
Abstract
Sulfur mustard (SM), a chemical warfare agent, is a strong alkylating compound that readily reacts with numerous biomolecules. The goal of the present work was to define and validate new biomarkers of exposure to SM that could be easily accessible in urine or plasma. Because investigations using SM are prohibited by the Organisation for the Prohibition of Chemical Weapons, we worked with 2-chloroethyl ethyl sulfide (CEES), a monofunctional analog of SM. We developed an ultra-high-pressure liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) approach to the conjugate of CEES to glutathione and two of its metabolites: the cysteine and the N-acetylcysteine conjugates. The N7-guanine adduct of CEES (N7Gua-CEES) was also targeted. After synthesizing the specific biomarkers, a solid-phase extraction protocol and a UHPLC-MS/MS method with isotopic dilution were optimized. We were able to quantify N7Gua-CEES in the DNA of HaCaT keratinocytes and of explants of human skin exposed to CEES. N7Gua-CEES was also detected in the culture medium of these two models, together with the glutathione and the cysteine conjugates. In contrast, the N-acetylcysteine conjugate was not detected. The method was then applied to plasma from mice cutaneously exposed to CEES. All four markers could be detected. Our present results thus validate both the analytical technique and the biological relevance of new, easily quantifiable biomarkers of exposure to CEES. Because CEES behaves very similar to SM, the results are promising for application to this toxic of interest. Graphical abstractKeywords
Funding Information
- Agence de l’Innovation de Défense“
- NRBC program of CEA
This publication has 64 references indexed in Scilit:
- Mechanisms of sulfur mustard analog 2-chloroethyl ethyl sulfide-induced DNA damage in skin epidermal cells and fibroblastsFree Radical Biology & Medicine, 2011
- Efficacy of Glutathione in Ameliorating Sulfur Mustard Analog-Induced Toxicity in Cultured Skin Epidermal Cells and in SKH-1 Mouse Skin In VivoThe Journal of pharmacology and experimental therapeutics, 2010
- Genetic loci influencing kidney function and chronic kidney diseaseNature Genetics, 2010
- Cysteine S-conjugate β-lyases: important roles in the metabolism of naturally occurring sulfur and selenium-containing compounds, xenobiotics and anticancer agentsAmino Acids, 2010
- The formation and biological significance of N7-guanine adductsMutation Research - Genetic Toxicology and Environmental Mutagenesis, 2009
- Glutathione dysregulation and the etiology and progression of human diseasesBiological Chemistry, 2008
- Biologically Relevant Chemical Reactions of N7-Alkylguanine Residues in DNAChemical Research in Toxicology, 2004
- γ-Glutamyl transpeptidase, a glutathionase: Its expression and function in carcinogenesisChemico-Biological Interactions, 1998
- THE CHEMISTRY OF 1,1′-THIOBIS(2-CHLOROETHANE) (SULPHUR MUSTARD) PART II.1 THE SYNTHESIS OF SOME CONJUGATES WITH CYSTEINE, N-ACETYLCYSTEINE AND N-ACETYLCYSTEINE METHYL ESTERPhosphorus, Sulfur, and Silicon and the Related Elements, 1992