Mitochondrial glutathione transporter SLC25A39 (SLC25A39)

The term Glutathione transporter refers to a diverse group of membrane proteins that facilitate the movement of glutathione (GSH), a critical antioxidant tripeptide, across cellular and organelle membranes. The most specific human protein identified with this name is the Mitochondrial glutathione transporter SLC25A39, which is essential for importing GSH into the mitochondria to maintain redox homeostasis and support iron-sulfur cluster biogenesis (UniProt Q9BZJ4; Nature 2021, 599:136-140). In the context of drug delivery, the term also describes a sodium-dependent glutathione transporter expressed on the blood-brain barrier (BBB), which is exploited by platforms like G-Technology to deliver therapeutics into the central nervous system via transporter-mediated transcytosis (Medicinal Chemistry Research 2024, 33:1281-1291). Additionally, the Multidrug resistance-associated protein 1 (ABCC1) is a well-characterized glutathione efflux transporter that contributes to chemotherapy resistance by pumping GSH and GSH-conjugates out of cancer cells (J. Biol. Chem. 2011, 286:34403-34411). Targeting these transporters offers therapeutic potential in oncology, where inhibiting SLC25A39 or ABCC1 can induce lethal oxidative stress in tumor cells, and in neurology, where BBB-targeting ligands enhance the delivery of neuroprotective agents (ScienceDaily 2021; MDPI 2024, 13:255).

Other names

SLC25A39Solute carrier family 25 member 39Multidrug resistance-associated protein 1 (ABCC1)MRP1Sodium-dependent glutathione transporterGSH transporterCGI-69Mitochondrial glutathione transporter 1GSHC1Glutathione-S-conjugate-translocating ATPase ABCC1

The mechanism of action for drugs targeting glutathione transporters involves either the utilization of the transporter for targeted delivery across the blood-brain barrier (transporter-mediated transcytosis) or the modulation of glutathione levels to influence cellular redox state and drug resistance. For example, glutathione-ligand-conjugated liposomes (G-Technology) bind to transporters on the blood-brain barrier to facilitate central nervous system entry, while inhibitors of transporters like ABCC1 prevent the efflux of glutathione and its conjugates, thereby sensitizing cancer cells to chemotherapy.