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Characterization and tissue localization of zebrafish homologs of the human ABCB1 multidrug transporter.

Authors :
Robey RW
Robinson AN
Ali-Rahmani F
Huff LM
Lusvarghi S
Vahedi S
Hotz JM
Warner AC
Butcher D
Matta J
Edmondson EF
Lee TD
Roth JS
Lee OW
Shen M
Tanner K
Hall MD
Ambudkar SV
Gottesman MM
Source :
Scientific reports [Sci Rep] 2021 Dec 17; Vol. 11 (1), pp. 24150. Date of Electronic Publication: 2021 Dec 17.
Publication Year :
2021

Abstract

Capillary endothelial cells of the human blood-brain barrier (BBB) express high levels of P-glycoprotein (P-gp, encoded by ABCB1) and ABCG2 (encoded by ABCG2). However, little information is available regarding ATP-binding cassette transporters expressed at the zebrafish BBB, which has emerged as a potential model system. We report the characterization and tissue localization of two genes that are similar to ABCB1, zebrafish abcb4 and abcb5. When stably expressed in HEK293 cells, both Abcb4 and Abcb5 conferred resistance to P-gp substrates; however, Abcb5 poorly transported doxorubicin and mitoxantrone compared to zebrafish Abcb4. Additionally, Abcb5 did not transport the fluorescent P-gp probes BODIPY-ethylenediamine or LDS 751, while they were transported by Abcb4. High-throughput screening of 90 human P-gp substrates confirmed that Abcb4 has an overlapping substrate specificity profile with P-gp. In the brain vasculature, RNAscope probes for abcb4 colocalized with staining by the P-gp antibody C219, while abcb5 was not detected. The abcb4 probe also colocalized with claudin-5 in brain endothelial cells. Abcb4 and Abcb5 had different tissue localizations in multiple zebrafish tissues, potentially indicating different functions. The data suggest that zebrafish Abcb4 functionally phenocopies P-gp and that the zebrafish may serve as a model to study the role of P-gp at the BBB.<br /> (© 2021. The Author(s).)

Details

Language :
English
ISSN :
2045-2322
Volume :
11
Issue :
1
Database :
MEDLINE
Journal :
Scientific reports
Publication Type :
Academic Journal
Accession number :
34921178
Full Text :
https://doi.org/10.1038/s41598-021-03500-8