Extracellular production of hydrogen selenide accounts for thiol-assisted toxicity of selenite against Saccharomyces cerevisiae.
Administration of selenium in humans has anticarcinogenic effects. However, the boundary between cancer-protecting and toxic levels of selenium is extremely narrow. The mechanisms of selenium toxicity need to be fully understood. In Saccharomyces cerevisiae, selenite in the millimolar range is well tolerated by cells. Here we show that the lethal dose of selenite is reduced to the micromolar range by the presence of thiols in the growth medium. Glutathione and selenite spontaneously react to produce several selenium-containing compounds (selenodiglutathione, glutathioselenol, hydrogen selenide, and elemental selenium) as well as reactive oxygen species. We studied which compounds in the reaction pathway between glutathione and sodium selenite are responsible for this toxicity. Involvement of selenodiglutathione, elemental selenium, or reactive oxygen species could be ruled out. In contrast, extracellular formation of hydrogen selenide can fully explain the exacerbation of selenite toxicity by thiols. Indeed, direct production of hydrogen selenide with D-cysteine desulfhydrase induces high mortality. Selenium uptake by S. cerevisiae is considerably enhanced in the presence of external thiols, most likely through internalization of hydrogen selenide. Finally, we discuss the possibility that selenium exerts its toxicity through consumption of intracellular reduced glutathione, thus leading to severe oxidative stress.
Tarze
Agathe
A
Laboratoire de Biochimie, UMR CNRS 7654, Département de Biologie, Ecole Polytechnique, 91128 Palaiseau Cedex, France.
Dauplais
Marc
M
Grigoras
Ioana
I
Lazard
Myriam
M
Ha-Duong
Nguyet-Thanh
NT
Barbier
Frédérique
F
Blanquet
Sylvain
S
Plateau
Pierre
P
D017209:Apoptosis; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000378:metabolism; D008956:Models, Chemical; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D017382:Reactive Oxygen Species; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D012643:Selenium / Q000378:metabolism; D018036:Selenium Compounds / Q000737:chemistry* / Q000378:metabolism; D018038:Sodium Selenite / Q000494:pharmacology* / Q000633:toxicity; D013481:Superoxides / Q000737:chemistry; D013879:Thioredoxins / Q000737:chemistry; D014969:Xanthine Oxidase / Q000378:metabolism
D017382:Reactive Oxygen Species; D018036:Selenium Compounds; D013481:Superoxides; D013879:Thioredoxins; D014969:Xanthine Oxidase; D005978:Glutathione; D012643:Selenium; D018038:Sodium Selenite; C026372:hydrogen selenide