title: An uncommon redox behavior sheds light on the cellular antioxidant properties of ergothioneine.
abstract: Ergothioneine (ESH), an aromatic thiol occurring in the human diet and which accumulates in particular cells, is believed to act as an antioxidant. However, its redox mechanism remains unclear and it does not seem to provide any advantage compared to other antioxidants, such as alkylthiols, which are better reducing agents and generally present in cells at higher levels. Here, we investigated by ESI-MS the products of ESH oxidation produced by neutrophils during oxidative burst and, to further elucidate ESH redox behavior, we also analyzed the oxidation products of the reaction of ESH with hypochlorite in cell-free solutions. Indeed, neutrophils are the main source of hypochlorite in humans. Furthermore, we also tested other biologically relevant oxidants, such as peroxynitrite and hydrogen peroxide. Our results indicate that treatment of human neutrophils with phorbol 12-myristate 13-acetate in the presence of ESH leads to a remarkable production of the sulfonated form (ESO3H), a compound never described before, and hercynine (EH), the desulfurated form of ESH. Similar results were obtained when ESH was subjected to cell-free oxidation in the presence of hypochlorite, as well as hydrogen peroxide or peroxynitrite. Furthermore, when the disulfide of ESH was reacted with those oxidants, we found that it was also oxidized, with production of EH and ESO3H, whose amount was dependent on the oxidant strength. These data reveal a unique ESH redox behavior, entirely different from that of alkylthiols, and suggest a mechanism, so far overlooked, through which ESH performs its antioxidant action in cells.
authors.affiliation: Dipartimento di Biochimica, Biofisica e Patologia Generale, Seconda Università degli Studi di Napoli, 7-80138 Napoli, Italy. Electronic address: luigi.servillo@unina2.it.
authors.forename: Luigi
authors.initials: L
authors.lastname: Servillo
authors.affiliation: Stazione Sperimentale per le Industrie delle Essenze e dei Derivati dagli Agrumi, Azienda Speciale della Camera di Commercio di Reggio Calabria, 12-89125 Reggio Calabria, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Castaldo
authors.affiliation: Dipartimento di Biochimica, Biofisica e Patologia Generale, Seconda Università degli Studi di Napoli, 7-80138 Napoli, Italy.
authors.forename: Rosario
authors.initials: R
authors.lastname: Casale
authors.affiliation: Dipartimento di Biochimica, Biofisica e Patologia Generale, Seconda Università degli Studi di Napoli, 7-80138 Napoli, Italy.
authors.forename: Nunzia
authors.initials: N
authors.lastname: D'Onofrio
authors.affiliation: Dipartimento di Biochimica, Biofisica e Patologia Generale, Seconda Università degli Studi di Napoli, 7-80138 Napoli, Italy.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Giovane
authors.affiliation: Stazione Sperimentale per le Industrie delle Essenze e dei Derivati dagli Agrumi, Azienda Speciale della Camera di Commercio di Reggio Calabria, 12-89125 Reggio Calabria, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Cautela
authors.affiliation: Dipartimento di Biochimica, Biofisica e Patologia Generale, Seconda Università degli Studi di Napoli, 7-80138 Napoli, Italy.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Balestrieri
mesh_terms: D000975:Antioxidants / Q000494:pharmacology*; D004880:Ergothioneine / Q000494:pharmacology*; D006801:Humans; D009504:Neutrophils / Q000187:drug effects; D010084:Oxidation-Reduction
chemical_list: D000975:Antioxidants; D004880:Ergothioneine
keywords: Ergothioneine; Ergothioneine sulfonic acid; Free radicals; Hercynine; Neutrophils; Oxidative burst; Oxidative stress