Format

Send to

Choose Destination
J Cereb Blood Flow Metab. 2020 Jan;40(1):116-125. doi: 10.1177/0271678X18808399. Epub 2018 Oct 22.

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

Author information

1
National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

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.

KEYWORDS:

Blood–brain barrier; detoxification; efflux transporter; glutathione conjugate; positron emission tomography

PMID:
30346895
PMCID:
PMC6928562
[Available on 2021-01-01]
DOI:
10.1177/0271678X18808399

Supplemental Content

Full text links

Icon for Atypon
Loading ...
Support Center