Glutathione efflux through an SLCO/OATP‐like transporter is necessary for the progression of FasL‐induced apoptosis in Jurkat cells

Apoptosis is characterized by the activation of specific biochemical pathways, from which intracellular glutathione [GSH] i depletion is an important hallmark. To date, neither the mechanisms involved in the reduction of [GSH] i , nor its relationship with the progression of apoptosis have been clearly elucidated. In this work, we studied the mechanism by which apoptosis induced by FasL reduces [GSH] I , and its connection with the progression of cell death program in Jurkat cells. A reduction in the total [GSH] i in response to FasL‐induced apoptosis was shown to occur in two stages. The first stage of [GSH] i loss was correlated with a decrease in cell size, increased Na + concentration, and plasma membrane depolarization. The second stage was coupled to intracellular Na + and K + loss and membrane blebbing. Significant levels of mRNA were detected in Jurkat cells, for several members of the ABCC/MRP and SLCO/OATP families of GSH‐efflux pumps. FasL‐induced GSH efflux was stimulated by organic substrates and inhibited by high concentrations of extracellular GSH consistent with the role of the SLCO/OATP transporters in GSH efflux. High GSH prevented the changes in ionic homeostasis, cell shrinkage and both the activation of the initiation and execution phases of apoptosis. We propose for the first time that [GSH] i efflux during FasL‐induced apoptosis occurs in two stages, and that it is mediated by an SLCO‐like transport mechanism. GSH loss is necessary for the activation of the cell death program