Transmembrane Domain Single-Nucleotide Polymorphisms Impair Expression and Transport Activity of ABC Transporter ABCG2

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http://hdl.handle.net/10138/215611

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Sjöstedt , N , van den Heuvel , J J M W , Koenderink , J B & Kidron , H 2017 , ' Transmembrane Domain Single-Nucleotide Polymorphisms Impair Expression and Transport Activity of ABC Transporter ABCG2 ' , Pharmaceutical Research , vol. 34 , no. 8 , pp. 1626-1636 . https://doi.org/10.1007/s11095-017-2127-1

Title: Transmembrane Domain Single-Nucleotide Polymorphisms Impair Expression and Transport Activity of ABC Transporter ABCG2
Author: Sjöstedt, Noora; van den Heuvel, Jeroen J. M. W.; Koenderink, Jan B.; Kidron, Heidi
Contributor: University of Helsinki, Faculty of Pharmacy
University of Helsinki, Faculty of Pharmacy
Date: 2017-08
Language: eng
Number of pages: 11
Belongs to series: Pharmaceutical Research
ISSN: 0724-8741
URI: http://hdl.handle.net/10138/215611
Abstract: To study the function and expression of nine naturally occurring single-nucleotide polymorphisms (G406R, F431L, S441N, P480L, F489L, M515R, L525R, A528T and T542A) that are predicted to reside in the transmembrane regions of the ABC transporter ABCG2. The transport activity of the variants was tested in inside-out membrane vesicles from Sf9 insect and human derived HEK293 cells overexpressing ABCG2. Lucifer Yellow and estrone sulfate were used as probe substrates of activity. The expression levels and cellular localization of the variants was compared to the wild-type ABCG2 by western blotting and immunofluorescence microscopy. All studied variants of ABCG2 displayed markedly decreased transport in both Sf9-ABCG2 and HEK293-ABCG2 vesicles. Impaired transport could be explained for some variants by altered expression levels and cellular localization. Moreover, the destructive effect on transport activity of variants G406R, P480L, M515R and T542A is, to our knowledge, reported for the first time. These results indicate that the transmembrane region of ABCG2 is sensitive to amino acid substitution and that patients harboring these ABCG2 variant forms could suffer from unexpected pharmacokinetic events of ABCG2 substrate drugs or have an increased risk for diseases such as gout where ABCG2 is implicated.
Subject: BCRP
genetic variant
interindividual variability
pharmacogenetics
SNP
CANCER-RESISTANCE-PROTEIN
BCRP GENE POLYMORPHISMS
IN-VITRO
LOCALIZATION
MUTATIONS
IDENTIFICATION
INHIBITION
BCRP/ABCG2
VARIANTS
CELLS
116 Chemical sciences
317 Pharmacy
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