title: Methylselenol formed by spontaneous methylation of selenide is a superior selenium substrate to the thioredoxin and glutaredoxin systems.
abstract: Naturally occurring selenium compounds like selenite and selenodiglutathione are metabolized to selenide in plants and animals. This highly reactive form of selenium can undergo methylation and form monomethylated and multimethylated species. These redox active selenium metabolites are of particular biological and pharmacological interest since they are potent inducers of apoptosis in cancer cells. The mammalian thioredoxin and glutaredoxin systems efficiently reduce selenite and selenodiglutathione to selenide. The reactions are non-stoichiometric aerobically due to redox cycling of selenide with oxygen and thiols. Using LDI-MS, we identified that the addition of S-adenosylmethionine (SAM) to the reactions formed methylselenol. This metabolite was a superior substrate to both the thioredoxin and glutaredoxin systems increasing the velocities of the nonstoichiometric redox cycles three-fold. In vitro cell experiments demonstrated that the presence of SAM increased the cytotoxicity of selenite and selenodiglutathione, which could neither be explained by altered selenium uptake nor impaired extra-cellular redox environment, previously shown to be highly important to selenite uptake and cytotoxicity. Our data suggest that selenide and SAM react spontaneously forming methylselenol, a highly nucleophilic and cytotoxic agent, with important physiological and pharmacological implications for the highly interesting anticancer effects of selenium.
authors.affiliation: Division of Pathology F46, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden. aristi.fernandes@ki.se
authors.forename: Aristi P
authors.initials: AP
authors.lastname: Fernandes
authors.forename: Marita
authors.initials: M
authors.lastname: Wallenberg
authors.forename: Valentina
authors.initials: V
authors.lastname: Gandin
authors.forename: Sougat
authors.initials: S
authors.lastname: Misra
authors.forename: Francesco
authors.initials: F
authors.lastname: Tisato
authors.forename: Cristina
authors.initials: C
authors.lastname: Marzano
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Rigobello
authors.forename: Sushil
authors.initials: S
authors.lastname: Kumar
authors.forename: Mikael
authors.initials: M
authors.lastname: Björnstedt
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology*; D001692:Biological Transport; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D004220:Disulfides / Q000378:metabolism; D054477:Glutaredoxins / Q000378:metabolism*; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D000432:Methanol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D008745:Methylation; D016566:Organoselenium Compounds / Q000378:metabolism* / Q000494:pharmacology; D010084:Oxidation-Reduction; D011485:Protein Binding; D012436:S-Adenosylmethionine / Q000378:metabolism / Q000494:pharmacology; D018036:Selenium Compounds / Q000378:metabolism* / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism; D013880:Thioredoxin-Disulfide Reductase / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D004220:Disulfides; D054477:Glutaredoxins; D016566:Organoselenium Compounds; D018036:Selenium Compounds; D013481:Superoxides; C017710:selenodiglutathione; D013879:Thioredoxins; C019003:methaneselenol; D012436:S-Adenosylmethionine; D045304:Cytochromes c; D013880:Thioredoxin-Disulfide Reductase; D005978:Glutathione; D000432:Methanol