Cloning and Functional Characterization of Dog OCT1 and OCT2: Another Step in Exploring Species Differences in Organic Cation Transporters
| Autor: | Marleen Julia Meyer, Simon Falk, Sarah Römer, Clarissa Prinzinger, Sabine Tacke, Joachim Geyer, Stefan Simm, Mladen Vassilev Tzvetkov |
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| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Organic Cation Transport Proteins
Organic Chemistry Organic Cation Transporter 1 Organic Cation Transporter 2 General Medicine Catalysis Computer Science Applications Inorganic Chemistry Mice Dogs HEK293 Cells Species Specificity Cations Animals Humans Cloning Molecular Physical and Theoretical Chemistry organic cation transporter SLC22A1 SLC22A2 species differences ortholog comparison gene structure metformin trospium fenoterol ipratropium butylscopolamine Molecular Biology Spectroscopy Fenoterol |
| Zdroj: | International Journal of Molecular Sciences; Volume 23; Issue 9; Pages: 5100 |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms23095100 |
| Popis: | OCT1 and OCT2 are polyspecific membrane transporters that are involved in hepatic and renal drug clearance in humans and mice. In this study, we cloned dog OCT1 and OCT2 and compared their function to the human and mouse orthologs. We used liver and kidney RNA to clone dog OCT1 and OCT2. The cloned and the publicly available RNA-Seq sequences differed from the annotated exon-intron structure of OCT1 in the dog genome CanFam3.1. An additional exon between exons 2 and 3 was identified and confirmed by sequencing in six additional dog breeds. Next, dog OCT1 and OCT2 were stably overexpressed in HEK293 cells and the transport kinetics of five drugs were analyzed. We observed strong differences in the transport kinetics between dog and human orthologs. Dog OCT1 transported fenoterol with 12.9-fold higher capacity but 14.3-fold lower affinity (higher KM) than human OCT1. Human OCT1 transported ipratropium with 5.2-fold higher capacity but 8.4-fold lower affinity than dog OCT1. Compared to human OCT2, dog OCT2 showed 10-fold lower transport of fenoterol and butylscopolamine. In conclusion, the functional characterization of dog OCT1 and OCT2 reported here may have implications when using dogs as pre-clinical models as well as for drug therapy in dogs. |
| Databáze: | OpenAIRE |
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