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Substrate-Dependent -Stimulation of Organic Cation Transporter 2 Activity. | LitMetric

Substrate-Dependent -Stimulation of Organic Cation Transporter 2 Activity.

Int J Mol Sci

CHU Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail)-UMR_S 1085, University Rennes, 35043 Rennes, France.

Published: November 2021

AI Article Synopsis

Article Abstract

The search of substrates for solute carriers (SLCs) constitutes a major issue, owing notably to the role played by some SLCs, such as the renal electrogenic organic cation transporter (OCT) 2 (), in pharmacokinetics, drug-drug interactions and drug toxicity. For this purpose, substrates have been proposed to be identified by their -inhibition and -stimulation properties towards transporter activity. To get insights on the sensitivity of this approach for identifying SLC substrates, 15 various exogenous and endogenous OCT2 substrates were analysed in the present study, using 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide (DiASP) as a fluorescent OCT2 tracer substrate. All OCT2 substrates -inhibited DiASP uptake in OCT2-overexpressing HEK293 cells, with IC values ranging from 0.24 µM (for ipratropium) to 2.39 mM (for dopamine). By contrast, only 4/15 substrates, i.e., acetylcholine, agmatine, choline and metformin, -stimulated DiASP uptake, with a full suppression of the -stimulating effect of metformin by the reference OCT2 inhibitor amitriptyline. An analysis of molecular descriptors next indicated that -stimulating OCT2 substrates exhibit lower molecular weight, volume, polarizability and lipophilicity than non--stimulating counterparts. Overall, these data indicated a rather low sensitivity (26.7%) of the -stimulation assay for identifying OCT2 substrates, and caution with respect to the use of such assay may therefore be considered.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8657912PMC
http://dx.doi.org/10.3390/ijms222312926DOI Listing

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