Selenium homeostasis and thioredoxin reductase induction at long term treatment with selenite in tumor preventive doses.

A57

Selenium has a documented tumor preventive effect in animal tumor models and in man.We have shown in our work that sodium selenite administered to rats in the drinking water inhibits the growth rate of preneoplastic and neoplastic liver lesions in a dose dependent way during the promotion and progression phases of the Salt and Farber model of experimental hepatocarcinogenesis. Life-long selenite treatment results in smaller liver lesions with reduced rate of cell proliferation and a longer life span compared to rats with no selenium supplementation. In our model the selenoenzyme thioredoxin reductase is heavily upregulated in prenoplastic and neoplastic lesions and we postulate the thioredoxin reductase is involved in the preventive mechanism. To study the long term kinetics of selenium uptake, distribution and elimination and to study the kinetics of selenium induction of thioredoxin reductase we have exposed Fisher 344 rats to sodium selenite in the drinking water in tumor preventive doses for 3 months and monitored selenium levels in blood and liver as well as the induction of thioredoxin reductase mRNA and enzyme activity in liver. 1 ppm sodium selenite in the drining water increases serum selenium levels slowly to a steady state at 600 ng/ml after 4 weeks of treatment. Liver accumulation of selenium is slower and reaches a plateau at 10 weeks. 5 ppm sodium selenite increase serum selenium levels rapidly, within the first day to the plateau level that the 1 ppm rats reach after 4-6 weeks. The selenium levels in the liver increases rapidly to a supersaturated level of 1000 ng/g liver and remains high for 1 week where after it is slowly decreasing to the level of the 1 ppm rats, where it remains. Thioredoxin reductase mRNA is rapidly induced by selenite.The induction is transient and the level is back to normal already after 5 days. The enzyme activity in elevated in a biphasic way reflecting the selenium levels in liver and blood. We conclude that selenium accumulates in the body at a dose dependent rate up to an apparent level of saturation. This plateau level in not dose dependent and kept constant in spite of further exposure. Thioredoxin reductase mRNA is rapidly and transiently induced by selenium. The protein of the active enzyme is also induced but stays up for several weeks and only slowly decreases to a steady state basal level within 6 to 10 weeks. The effect of selenium on selenium levels and induced enzyme activity is only evident during the initial weeks of a long term treatment and cannot explain the tumor preventive effects. It is our believe that the adaptation to an increased selenium availability is a physiologic adaptation to a toxic exposure of selenium, a toxicity that may represent the tumor preventive mechanism affecting cells with an overexpression of thioredoxin reductase making them more sensitive to selenium toxicity than the surrounding hepatocytes.