Enhanced cadmium cytotoxicity in A549 cells with reduced glutathione levels is due to neither enhanced cadmium accumulation nor reduced metallothionein synthesis

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Abstract
Glutathione (GSH) depletion sensitizes human lung carcinoma (A549-727) cells to the cytotoxic effects of Cd++. The effects of GSH depletion on Cd++ accumulation and Cd+-induced metallothionein (MT) content were investigated to determine the possible role of these Cd++ responses in the sensitization process. Cellular GSH was depleted to 20% to 25% of control levels with buthionine sulfoximine (BSO), or diethyl maleate (DEM), respectively. Neither treatment significantly affected Cd++-induced accumulation of exogenous35s-cysteine into intracellular MT in a dose-dependent fashion. The results indicate that neither enhanced Cd++ accumulation nor reduced MT synthesis plays a primary role in affecting enhanced Cd++ cytotoxicity in A549 cells with reduced GSH levels. Although BSO inhibition of GSH synthesis enhanced MT synthesis, it sensitized the cells to Cd++, which suggests an additive effect of GSH and MT in cadmium cytoprotection. This observation also raises the possibility that intracellular cysteine levels limit Cd++-induced MT accumulation rates.