Mechanisms of glutathione-conjugate efflux from the brain into blood: Involvement of multiple transporters in the course.
J Cereb Blood Flow Metab
; 40(1): 116-125, 2020 01.
Article
em En
| MEDLINE
| ID: mdl-30346895
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-[11C]methylpurine ([11C]1), which enters the brain and is converted into its glutathione conjugate, S-(7-[11C]methylpurin-6-yl)glutathione ([11C]2). In mice of control and knockout of P-glycoprotein/breast cancer resistance protein and multidrug resistance-associated protein 2 ([Mrp2]-/-), [11C]2 formed in the brain was rapidly cleared, with no significant difference in efflux rate. In contrast, [11C]2 formed in the brain of Mrp1-/- mice was slowly cleared, whereas [11C]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 [11C]2 efflux across cell membranes, but not BBB. Efflux rate of [11C]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 [11C]2 efflux from the brain. Mrp1 may contribute to [11C]2 efflux from brain parenchymal cells, while extracellular [11C]2 is likely cleared across the BBB, partly by Oat3 and Mrp4.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Proteínas de Membrana Transportadoras
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Glutationa
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article