Metallothionein, glutathione, and cystine transport in pulmonary artery endothelial cells and NIH/3T3 cells.

Both glutathione (gamma-glutamylcysteinylglycine; GSH) and the metalloprotein metallothionein (MT) are composed of approximately one-third cysteine. Both have antioxidant activity and are induced by oxidant stresses and heavy metals. Intracellular cysteine levels may depend on uptake and reduction of extracellular cystine. GSH synthesis can be limited by the activity of the xc- cystine transport system, which is induced by oxidants and other stresses. MT is induced by treatments that also increase GSH levels and may compete with GSH for intracellular cysteine. We investigated the induction of MT and GSH and cystine transport in NIH/3T3 cells and bovine pulmonary artery endothelial cells exposed to cadmium (Cd) or arsenite. Cd and arsenite increased MT and GSH in both cells. Increases in MT and GSH were accompanied by increases in cystine uptake. Inhibition of cystine transport by glutamate decreased GSH levels and blocked Cd-induced GSH increases in both cell types. MT levels were not significantly affected, suggesting that MT synthesis is less sensitive to intracellular cysteine levels than GSH synthesis.