Abstract
Accumulation of detrimental glutathione-conjugated metabolites in the brain potentially causes neurological disorders, and must therefore be exported from the brain. However, in vivo mechanisms of glutathione-conjugates efflux from the brain remain unknown. We investigated the involvement of transporters in glutathione-conjugates efflux using 6-bromo-7-[(11)C]methylpurine ([(11)C]1), which enters the brain and is converted into its glutathione conjugate, S-(7-[(11)C]methylpurin-6-yl)glutathione ([(11)C]2). In mice of control and knockout of P-glycoprotein/breast cancer resistance protein and multidrug resistance-associated protein 2 ([Mrp2](-/-)), [(11)C]2 formed in the brain was rapidly cleared, with no significant difference in efflux rate. In contrast, [(11)C]2 formed in the brain of Mrp1(-/-) mice was slowly cleared, whereas [(11)C]2 microinjected into the brain of control and Mrp1(-/-) mice was 75% cleared within 60 min, with no significant difference in efflux rate. These suggest that Mrp1 contributes to [(11)C]2 efflux across cell membranes, but not BBB. Efflux rate of [(11)C]2 formed in the brain was significantly lower in Mrp4(-/-) and organic anion transporter 3 (Oat3)(-/-) mice compared with control mice. In conclusion, Mrp1, Oat3, and Mrp4 mediate [(11)C]2 efflux from the brain. Mrp1 may contribute to [(11)C]2 efflux from brain parenchymal cells, while extracellular [(11)C]2 is likely cleared across the BBB, partly by Oat3 and Mrp4.