Influence of intracellular glutathione on selenite-mediated growth inhibition of canine mammary tumor cells.

The present studies demonstrate that the ability of supplemental selenite to alter the in vitro growth of canine mammary tumor cell line 13 was dependent on the quantity and duration of selenium exposure and on the culture density. Exposure to 3.2 microM selenite did not significantly alter growth but led to an increase in intracellular glutathione (GSH). The severity of growth inhibition between 3.2 and 9.6 microM selenite was dependent on the duration of exposure and culture density. The toxicity of selenite generally increased as the culture density increased. Likewise, changes in intracellular GSH were dependent on the quantity and duration of selenite exposure and the culture density. Depressing intracellular GSH by increasing the culture density or by incubating with buthionine sulfoximine; a specific inhibitor of gamma-glutamyl cysteine synthetase, increased the severity of growth inhibition caused by selenite and markedly increased cellular retention of selenium. Nevertheless, marked cellular retention of selenium did not occur until growth was inhibited by more than 50%. The present studies revealed that the log of the molar ratio of GSH to selenium correlated negatively with the severity of growth inhibition (P less than 0.0001). These studies suggest that cellular toxicity of selenite is dependent on the regulation of the GSH:selenium ratio. An inability to regulate this ratio likely leads to the accumulation of toxic seleno compounds.