The Effect of Single Nucleotide Variations in the Transmembrane Domain of OATP1B1 on in vitro Functionality

Show full item record



Permalink

http://hdl.handle.net/10138/337027

Citation

Kiander , W , Vellonen , K-S , Malinen , M M , Gynther , M , Hagström , M , Bhattacharya , M , Auriola , S , Koenderink , J B & Kidron , H 2021 , ' The Effect of Single Nucleotide Variations in the Transmembrane Domain of OATP1B1 on in vitro Functionality ' , Pharmaceutical Research , vol. 38 , no. 10 , pp. 1663-1675 . https://doi.org/10.1007/s11095-021-03107-8

Title: The Effect of Single Nucleotide Variations in the Transmembrane Domain of OATP1B1 on in vitro Functionality
Author: Kiander, Wilma; Vellonen, Kati-Sisko; Malinen, Melina M.; Gynther, Mikko; Hagström, Marja; Bhattacharya, Madhushree; Auriola, Seppo; Koenderink, Jan B.; Kidron, Heidi
Contributor organization: Divisions of Faculty of Pharmacy
Division of Pharmaceutical Biosciences
Drug Delivery Unit
Drug Research Program
Date: 2021-10
Language: eng
Number of pages: 13
Belongs to series: Pharmaceutical Research
ISSN: 0724-8741
DOI: https://doi.org/10.1007/s11095-021-03107-8
URI: http://hdl.handle.net/10138/337027
Abstract: Purpose Organic Anion Transporting Polypeptide 1B1 (OATP1B1) mediates hepatic influx and clearance of many drugs, including statins. The SLCO1B1 gene is highly polymorphic and its function-impairing variants can predispose patients to adverse effects. The effects of rare genetic variants of SLCO1B1 are mainly unexplored. We examined the impact of eight naturally occurring rare variants and the well-known SLCO1B1 c.521C > T (V174A) variant on in vitro transport activity, cellular localization and abundance. Methods Transport of rosuvastatin and 2,7-dichlorofluorescein (DCF) in OATP1B1 expressing HEK293 cells was measured to assess changes in activity of the variants. Immunofluorescence and confocal microscopy determined the cellular localization of OATP1B1 and LC-MS/MS based quantitative targeted absolute proteomics analysis quantified the amount of OATP1B1 in crude membrane fractions. Results All studied variants, with the exception of P336R, reduced protein abundance to varying degree. V174A reduced protein abundance the most, over 90% compared to wild type. Transport function was lost in G76E, V174A, L193R and R580Q variants. R181C decreased activity significantly, while T345M and L543W retained most of wild type OATP1B1 activity. P336R showed increased activity and H575L decreased the transport of DCF significantly, but not of rosuvastatin. Decreased activity was interrelated with lower absolute protein abundance in the studied variants. Conclusions Transmembrane helices 2, 4 and 11 appear to be crucial for proper membrane localization and function of OATP1B1. Four of the studied variants were identified as loss-of-function variants and as such could make the individual harboring these variants susceptible to altered pharmacokinetics and adverse effects of substrate drugs.
Subject: TRANSPORTING POLYPEPTIDE 1B1
SLCO1B1 POLYMORPHISM
INDUCED MYOPATHY
C SLC21A6
VARIANTS
EXPRESSION
DRUG
PHARMACOKINETICS
IDENTIFICATION
SUPERFAMILY
116 Chemical sciences
317 Pharmacy
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


Files in this item

Total number of downloads: Loading...

Files Size Format View
Kiander2021_Art ... tOfSingleNucleotideVar.pdf 2.008Mb PDF View/Open

This item appears in the following Collection(s)

Show full item record