Non-oxidative loss of glutathione in apoptosis via GSH extrusion.

Reduced glutathione (GSH) has been hypothesized to play a role in the rescue of cells from apoptosis, by buffering an endogenously induced oxidative stress. We correlated GSH levels and apoptosis in U937 human monocytic cells induced to apoptosis by different agents. All treatments led to depletion of GSH concomitant with the onset of apoptosis. The loss was due to extrusion of GSH outside the cell, while GSSG was not accumulated in the apoptosing cells, nor was it found in the extracellular medium. Modulation of intracellular GSH level did not influence the overall extent of apoptosis. We conclude that glutathione loss in apoptosis is not necessarily preceded by an oxidative stress, and that GSH depletion alone is not sufficient to lead cells to apoptosis.