title: A guanine-ethylthioethyl-glutathione adduct as a major DNA lesion in the skin and in organs of mice exposed to sulfur mustard.
abstract: Sulfur mustard (SM) is an old chemical warfare but it remains a threat to both militaries and civilians. SM mainly targets skin, eyes and lungs and diffuses to internal organs. At the molecular level, SM is able to damage DNA through the formation of monoadducts and biadduct. Glutathione (GSH) is another critical target of SM in cells since it is part of the detoxification mechanism against alkylating agents. In the present work, we investigated whether SM could form covalent bonds simultaneously with a DNA base and the sulfhydryl group of GSH. The expected guanine adduct, S-[2-(N7-guanyl)-ethylthioethyl]-glutathione (N7Gua-ETE-GSH), was synthesized and detected in several tissues of SKH-1 mice exposed to 60mg/kg of SM in the dorsal-lumbar region. N7Gua-ETE-GSH was detected in all organs studied, except in the liver. The tissue exhibiting the highest levels of N7Gua-ETE-GSH was skin, followed by brain, lungs, kidneys and spleen. N7Gua-ETE-GSH was detected in skin, brain and lungs as long as two weeks after exposure. The persistence was less in other organs. The observation of the formation of N7Gua-ETE-GSH in vivo confirms the variety of damages induced by SM in DNA. It also provides another example of the formation of DNA adducts involving glutathione following in vivo exposure to bifunctional alkylating compounds.
authors.affiliation: Univ. Grenoble Alpes, INAC, LCIB, LAN, F-38000 Grenoble, France; CEA, INAC, SCIB, LAN, F-38000 Grenoble, France; Département de Toxicologie et Risques Chimiques, Unité de Brûlure Chimique, Institut de Recherche Biomédicale des Armées, Antenne de La Tronche, BP87, F-38702 La Tronche Cedex, France.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Batal
authors.affiliation: Univ. Grenoble Alpes, INAC, LCIB, LAN, F-38000 Grenoble, France; CEA, INAC, SCIB, LAN, F-38000 Grenoble, France.
authors.forename: Silvestre
authors.initials: S
authors.lastname: Rebelo-Moreira
authors.affiliation: Univ. Grenoble Alpes, INAC, LCIB, LAN, F-38000 Grenoble, France; CEA, INAC, SCIB, LAN, F-38000 Grenoble, France.
authors.forename: Nadège
authors.initials: N
authors.lastname: Hamon
authors.affiliation: Univ. Grenoble Alpes, INAC, LCIB, LAN, F-38000 Grenoble, France; CEA, INAC, SCIB, LRM, F-38000 Grenoble, France.
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: Bayle
authors.affiliation: Département de Toxicologie et Risques Chimiques, Unité de Brûlure Chimique, Institut de Recherche Biomédicale des Armées, Antenne de La Tronche, BP87, F-38702 La Tronche Cedex, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Mouret
authors.affiliation: Département de Toxicologie et Risques Chimiques, Unité de Brûlure Chimique, Institut de Recherche Biomédicale des Armées, Antenne de La Tronche, BP87, F-38702 La Tronche Cedex, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Cléry-Barraud
authors.affiliation: Département de Toxicologie et Risques Chimiques, Unité de Brûlure Chimique, Institut de Recherche Biomédicale des Armées, Antenne de La Tronche, BP87, F-38702 La Tronche Cedex, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Boudry
authors.affiliation: Univ. Grenoble Alpes, INAC, LCIB, LAN, F-38000 Grenoble, France; CEA, INAC, SCIB, LAN, F-38000 Grenoble, France. Electronic address: thierry.douki@cea.fr.
authors.forename: Thierry
authors.initials: T
authors.lastname: Douki
mesh_terms: D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D018736:DNA Adducts / Q000737:chemistry*; D005978:Glutathione / Q000737:chemistry*; D006147:Guanine / Q000737:chemistry*; D007668:Kidney / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D008168:Lung / Q000187:drug effects; D008297:Male; D051379:Mice; D009151:Mustard Gas / Q000633:toxicity*; D012867:Skin / Q000187:drug effects*; D013154:Spleen / Q000187:drug effects
chemical_list: D000477:Alkylating Agents; D018736:DNA Adducts; D006147:Guanine; D005978:Glutathione; D009151:Mustard Gas
keywords: Bifunctional alkylating agent; DNA adducts; Glutathione; Skin toxicity; Sulfur mustard