The role of thioredoxin reductase activity in selenium-induced cytotoxicity.
The selenoprotein thioredoxin reductase is a key enzyme in selenium metabolism, reducing selenium compounds and thereby providing selenide to synthesis of all selenoproteins. We evaluated the importance of active TrxR1 in selenium-induced cytotoxicity using transfected TrxR1 over-expressing stable Human Embryo Kidney (HEK-293) cells and modulation of activity by pretreatment with low concentration of selenite. Treatment with sodium selenite induced cytotoxity in a dose-dependent manner in both TrxR1 over-expressing and control cells. However, TrxR1 over-expressing cells, which were preincubated for 72h with 0.1 microM selenite, were significantly more resistant to selenite cytotoxicity than control cells. To demonstrate the early effects of selenite on behaviour of HEK-293 cells, we also investigated the influence of this compound on cell motility. We observed inhibition of cell motility by 50 microM selenite immediately after administration. Moreover, TrxR1 over-expressing cells preincubated with a low concentration of selenite were more resistant to the inhibitory effect of 50 microM selenite than those not preincubated. It was also observed that the TrxR over-expressing cells showed higher TrxR1 activity than control cells and the preincubation of over-expressing cells with 0.1 microM selenite induced further significant increase in the activity of TrxR1. On the other hand, we demonstrated that TrxR1 over-expressing cells showed decreased glutathione peroxidase activity compared to control cells. These data strongly suggest that TrxR1 may be a crucial enzyme responsible for cell resistance against selenium cytotoxicity.
Madeja
Zbigniew
Z
Department of Laboratory Medicine, Division of Pathology, F46, Karolinska Institutet, Karolinska University Hospital in Huddinge, SE-141 86 Stockholm, Sweden.
Sroka
Jolanta
J
Nyström
Christina
C
Björkhem-Bergman
Linda
L
Nordman
Tomas
T
Damdimopoulos
Anastasios
A
Nalvarte
Ivan
I
Eriksson
Lennart C
LC
Spyrou
Giannis
G
Olsson
Jerker M
JM
Björnstedt
Mikael
M
D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D012643:Selenium / Q000633:toxicity*; D013880:Thioredoxin-Disulfide Reductase / Q000378:metabolism* / Q000502:physiology
D013880:Thioredoxin-Disulfide Reductase; D012643:Selenium