Multidrug resistance-associated protein 1 as a major mediator of basal and apoptotic glutathione release.
The proteins responsible for reduced glutathione (GSH) export under both basal conditions and in cells undergoing apoptosis have not yet been identified, although recent studies implicate some members of the multidrug resistance-associated protein family (MRP/ABCC) in this process. To examine the role of MRP1 in GSH release, the present study measured basal and apoptotic GSH efflux in HEK293 cells stably transfected with human MRP1. MRP1-overexpressing cells had lower intracellular GSH levels and higher levels of GSH release, under both basal conditions and after apoptosis was induced with either Fas antibody or staurosporine. Despite the enhanced GSH efflux in MRP1-overexpressing cells, intracellular GSH levels were not further depleted when cells were treated with Fas antibody or staurosporine, suggesting an increase in GSH synthesis. MRP1-overexpressing cells were also less susceptible to apoptosis, suggesting that the stable intracellular GSH levels may have protected cells from death. Overall, these results demonstrate that basal and apoptotic GSH release are markedly enhanced in cells overexpressing MRP1, suggesting that MRP1 plays a key role in these processes. The enhanced GSH release, with a concurrent decrease of intracellular GSH, appears to be necessary for the progression of apoptosis.
Marchan
Rosemarie
R
Department of Environmental Medicine, Box EHSC, University of Rochester School of Medicine, 575 Elmwood Avenue, Rochester, NY 14642, USA.
Hammond
Christine L
CL
Ballatori
Nazzareno
N
D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D002460:Cell Line; D003513:Cycloheximide / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism; D005452:Fluoresceins / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D017997:Leukotriene C4 / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000378:metabolism; D019311:Staurosporine / Q000378:metabolism; D014750:Vincristine / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D003513:Cycloheximide; D004791:Enzyme Inhibitors; D005452:Fluoresceins; D005978:Glutathione; D017997:Leukotriene C4; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011500:Protein Synthesis Inhibitors; D019311:Staurosporine; D014750:Vincristine; C007740:fluorexon; C421109:multidrug resistance-associated protein 1