BUTHIONINE SULFOXIMINE SPARES INTRACELLULAR GLUTAMATE - A POSSIBLE MECHANISM FOR CELL-GROWTH STIMULATION

Buthionine sulfoximine (BSO), a selective inhibitor of glutathione (GS H) synthesis, has a dual effect on proliferation of human lung carcino ma A549 cells, i.e., at low concentrations it stimulates and at higher concentrations it inhibits A549 cell proliferation. This study was un dertaken to test the hypothesis that BSO, by inhibiting the synthesis of GSH, spares its constituent amino acids, particularly glutamate, an d thereby stimulates cell proliferation. Treatment of A549 cells with BSO significantly increased intracellular glutamate levels, while it d ecreased cellular GSH levels. To determine whether the increased gluta mate level is responsible for the BSO-stimulated cell proliferation, A 549 cells were cultured in glutamine-deficient Dulbecco's modified Eag le's medium. These cells did not proliferate in this medium unless glu tamine (4 mM) was supplemented. When glutamine was replaced by glutama te in the medium the cells were also stimulated to proliferate, althou gh this stimulation was not as effective as that of glutamine. Cystein e and its cellular delivery system L-2-oxothiazolidine-4-carboxylate d id not stimulate cell proliferation even though BSO would also increas e cellular cysteine levels. The results obtained suggest that the BSO- increased cellular glutamate level is likely responsible for the BSO g rowth-stimulating effect.