Mechanisms of glutathione-conjugate efflux from the brain into blood: Involvement of multiple transporters in the course.

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-[C]methylpurine ([C]), which enters the brain and is converted into its glutathione conjugate, -(7-[C]methylpurin-6-yl)glutathione ([C]). In mice of control and knockout of P-glycoprotein/breast cancer resistance protein and multidrug resistance-associated protein 2 ([]), [C] formed in the brain was rapidly cleared, with no significant difference in efflux rate. In contrast, [C] formed in the brain of 1 mice was slowly cleared, whereas [C] microinjected into the brain of control and mice was 75% cleared within 60 min, with no significant difference in efflux rate. These suggest that Mrp1 contributes to [C] efflux across cell membranes, but not BBB. Efflux rate of [C] formed in the brain was significantly lower in and organic anion transporter 3 () mice compared with control mice. In conclusion, Mrp1, Oat3, and Mrp4 mediate [C] efflux from the brain. Mrp1 may contribute to [C] efflux from brain parenchymal cells, while extracellular [C] is likely cleared across the BBB, partly by Oat3 and Mrp4.