EXCESS SELENIUM: METABOLIC EFFECTS AND RELATION TO CELL PROLIFERATION AND CARCINOGENESIS

This thesis has examined the biological and biochemical basis by which excess selenium (Se) exerts anti-carcinogenic effects. The work has focused on three major points: (1) can Se affect hepatocarcinogenesis independent of alterations in carcinogen metabolism and if so, how? (2) does excess Se affect cell proliferation and if so, what stages of the mammalian cell cycle are affected? and (3) are alterations in cellular glutathione metabolism responsible for the observed cell damage and anti-carcinogenic effects of excess Se?;Experiments in vivo using regenerating liver and in vitro with established cell lines demonstrated that high Se decreased cell proliferation using autoradiography and microscopy as quantitative methods. Cell cycle kinetic analysis using fluorescence flow cytometry and microscopy showed that all stages of the mammalian cell cycle except mitosis were affected by high Se.;Experiments in vivo and in vitro demonstrated that high Se caused a significant increase in hepatic and cellular oxidized glutathione (GSSG) as well as the oxidized to reduced (GSH) glutathione ratio, an increase which precedes "adaptive" increases in GSH. Glucose-6-phosphate dehydrogenase and glutathione reductase activities as well as the NADP to NADPH ratio were also significantly increased with high Se substantiating the claim that Se causes a shift in hepatic glutathione status towards a more oxidized state.;The results presented in this thesis demonstrate that excess Se can decrease cell proliferation and this serves as a plausible explanation for the decreased growth of "pre-neoplastic" lesions observed with high Se. Increased cellular GSSG or GSSG/GSH ratio may be responsible for the decreased proliferation. High Se may also enhance carcinogenesis if fed in conjunction with tumor promoters or if adaptive liver growth occurs in response to high Se.;Concerning Se's effect on hepatocarcinogenesis in rats, 3.0 and 6.0 ppm dietary Se as Na(,2)SeO(,3) (high Se) decreased the growth of histochemically identified hepatic "pre-neoplastic" foci induced by the hepatocarcinogens diethylnitrosamine or N-acetylaminofluorene compared to 0.1 ppm Se but did not cause repair or removal of potential cancerous lesions. These results suggest an inhibitory or delaying effect of Se on cell proliferation. In addition, the Se effect on growth of foci were sometimes temporary and reversible depending on the dose and duration of Se feeding.