Dissociation of the genotoxic and growth inhibitory effects of selenium.
The effects of forms of selenium compounds that enter the cellular selenium metabolic pathway at different points were investigated in a mouse mammary carcinoma cell line. The goal of these experiments was to determine if the genotoxicity of selenium, defined as its ability to induce DNA single-strand breaks, could be dissociated from activities proposed to account for its cancer inhibitory activity. The results demonstrated that growth inhibition, measured as inhibition of cell proliferation and induction of cell death, was induced by all the forms of selenium evaluated. However, sodium selenite and sodium selenide, which are metabolized predominantly to hydrogen selenide, caused the rapid induction of DNA single-strand breaks as an early event that preceded growth inhibition. Interestingly methylselenocyanate and Se-methylselenocysteine, which are initially metabolized predominantly to methylselenol, induced growth inhibition in the absence of DNA single-strand breakage. Differences in the time course of selenium retention, in the occurrence of membrane damage, and in the induction of morphological changes by selenite versus methylselenocyanate were noted. Collectively, these data indicate that different pathways affecting cell proliferation and cell death are induced depending on whether selenium undergoes metabolism predominantly to hydrogen selenide or to methylselenol.
Lu
J
J
AMC Cancer Research Center, Denver, CO 80214, USA.
Jiang
C
C
Kaeck
M
M
Ganther
H
H
Vadhanavikit
S
S
Ip
C
C
Thompson
H
H
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D003545:Cysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D004277:DNA, Single-Stranded / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D051379:Mice; D016566:Organoselenium Compounds / Q000494:pharmacology; D012643:Selenium / Q000494:pharmacology*; D018036:Selenium Compounds / Q000494:pharmacology; D017279:Selenocysteine / Q000031:analogs & derivatives; D018038:Sodium Selenite / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D004277:DNA, Single-Stranded; D016566:Organoselenium Compounds; D018036:Selenium Compounds; D017279:Selenocysteine; C037341:sodium selenide; D012643:Selenium; D018038:Sodium Selenite; D003545:Cysteine; C002979:selenomethylselenocysteine