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Bitte verwenden Sie diesen Link, wenn Sie dieses Dokument zitieren oder verlinken wollen: https://nbn-resolving.org/urn:nbn:de:gbv:9-opus-45839

Effects of a Common Eight Base Pairs Duplication at the Exon 7-Intron 7 Junction on Splicing, Expression, and Function of OCT1

  • Organic cation transporter 1 (OCT1, SLC22A1) is localized in the sinusoidal membrane of human hepatocytes and mediates hepatic uptake of weakly basic or cationic drugs and endogenous compounds. Common amino acid substitutions in OCT1 were associated with altered pharmacokinetics and efficacy of drugs like sumatriptan and fenoterol. Recently, the common splice variant rs35854239 has also been suggested to affect OCT1 function. rs35854239 represents an 8 bp duplication of the donor splice site at the exon 7-intron 7 junction. Here we quantified the extent to which this duplication affects OCT1 splicing and, as a consequence, the expression and the function of OCT1. We used pyrosequencing and deep RNA-sequencing to quantify the effect of rs35854239 on splicing after minigene expression of this variant in HepG2 and Huh7 cells and directly in human liver samples. Further, we analyzed the effects of rs35854239 on OCT1 mRNA expression in total, localization and activity of the resulting OCT1 protein, and on the pharmacokinetics of sumatriptan and fenoterol. The 8 bp duplication caused alternative splicing in 38% (deep RNA-sequencing) to 52% (pyrosequencing) of the minigene transcripts when analyzed in HepG2 and Huh7 cells. The alternatively spliced transcript encodes for a truncated protein that after transient transfection in HEK293 cells was not localized in the plasma membrane and was not able to transport the OCT1 model substrate ASP+. In human liver, however, the alternatively spliced OCT1 transcript was detectable only at very low levels (0.3% in heterozygous and 0.6% in homozygous carriers of the 8 bp duplication, deep RNA-sequencing). The 8 bp duplication was associated with a significant reduction of OCT1 expression in the human liver, but explained only 9% of the general variability in OCT1 expression and was not associated with significant changes in the pharmacokinetics of sumatriptan and fenoterol. Therefore, the rs35854239 variant only partially changes splicing, causing moderate changes in OCT1 expression and may be of only limited therapeutic relevance.

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Author: Sarah Römer, Marleen J. Meyer, Kathrin Klein, Lennart V. Schneider, Johannes Matthaei, Ana Tzvetkova, Joanna Łapczuk-Romańska, Jochen Gaedcke, Marek Droździk, Jürgen Brockmöller, Anne T. Nies, Mladen V. Tzvetkov
URN:urn:nbn:de:gbv:9-opus-45839
DOI:https://doi.org/doi: 10.3389/fphar.2021.661480
ISSN:1663-9812
Parent Title (English):Frontiers in Pharmacology
Publisher:Frontiers Media S.A.
Place of publication:Lausanne
Document Type:Article
Language:English
Date of first Publication:2021/05/07
Release Date:2021/06/27
Tag:SLC22A1; allelic expression imbalance (AEI); fenoterol; ins/del variant; minigene; organic cation transporter 1; pharmacokinetics; sumatriptan
GND Keyword:-
Volume:12
Article Number:661480
Page Number:14
Faculties:Universitätsmedizin / Institut für Pharmakologie
Licence (German):License LogoCreative Commons - Namensnennung