Induction of the mitochondrial permeability transition by selenium compounds mediated by oxidation of the protein thiol groups and generation of the superoxide.
The cancer chemopreventive effect of selenium compounds cannot be fully explained by the role of selenium as a component of antioxidant enzymes, suggesting that other mechanisms, such as thiol oxidation or free radical generation, also underlie this effect. The toxicities of six different selenium compounds (selenite, selenate, selenocystine, selenocystamine, selenodioxide, and selenomethionine) have now been compared in HepG2 human hepatoma cells and isolated rat liver mitochondria. Selenite, selenocystine, and selenodioxide induced apoptosis in HepG2 cells and mediated oxidation of protein thiol groups in both HepG2 cells and isolated mitochondria. Selenocystamine oxidized protein thiol groups in isolated mitochondria and crude extracts of HepG2 cells but not in intact HepG2 cells, suggesting that this compound is not able to cross the cell membrane. The selenium compounds capable of oxidizing thiol groups also induced the mitochondrial permeability transition (MPT) in isolated mitochondria. Furthermore, they generated the superoxide (O(2) .-) on reaction with glutathione in the presence of mitochondria, and an O(2) .-) scavenger inhibited their induction of the MPT. These results suggest that the pro-apoptotic action of selenium compounds is mediated by both thiol oxidation and the generation of O(2) .-), both of which contribute to opening of the MPT pore.
Kim
Tae-Soo
TS
School of Life Sciences and Biotechnology, Korea University, 15-Ka, Anam-Dong, Sungbuk-ku, 136-701 Seoul, South Korea.
Yun
Byung Yup
BY
Kim
Ick Young
IY
D003538:Cystamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003553:Cystine / Q000031:analogs & derivatives* / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D008933:Mitochondrial Swelling / Q000187:drug effects; D016566:Organoselenium Compounds / Q000494:pharmacology; D010084:Oxidation-Reduction; D010539:Permeability / Q000187:drug effects*; D012643:Selenium / Q000737:chemistry / Q000494:pharmacology*; D012645:Selenomethionine / Q000494:pharmacology; D018038:Sodium Selenite / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
D016566:Organoselenium Compounds; D013438:Sulfhydryl Compounds; D013481:Superoxides; C009226:selenocystine; C014807:selenocystamine; D003553:Cystine; D045304:Cytochromes c; D012645:Selenomethionine; D012643:Selenium; D018038:Sodium Selenite; D003538:Cystamine