Effect of 1022C>T and 1222A>G genetic polymorphisms of SLC22A1 gene on substrates binding to human organic cation transporter 1
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Date
2020-09
Journal Title
Journal ISSN
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Publisher
Open Science Publishers LLP
Abstract
Human organic cation transporter 1 (hOCT1) is a transmembrane influx transporter protein encoded by the SLC22A1gene. hOCT1 plays a pivotal role in the hepatocellular and renal uptake of several xenobiotics and endogenoussubstrates. The human SLC22A1 gene is highly polymorphic. Non-synonymous single nucleotide polymorphisms(SNPs) of the human SLC22A1 gene tend to impair the transmembrane conductance of substrates by hOCT1. Herein,we describe the effect of 1022C>T and 1222A>G variations in the human SLC22A1 gene on hOCT1 structure andsubstrate binding. The three-dimensional (3D) structures of hOCT1 variants were ab initio models using the iTASSERserver, and drug-binding residues of the transmembrane domain were predicted using the Prankweb server. Substratebinding was analyzed by molecular docking using AutoDock 4.2.6. Amino acid residues, crucial for substrate bindingand transport, were altered in Met408Val and Pro341Leu variants and were suggestive of conformational changeinduced by 1022C>T and 1222A>G SNPs. Moreover, a statistically significant difference was observed betweenthe binding affinities of substrates to wild and mutant variants. Therefore, it is evident that 1022C>T and 1222A>Gnon-synonymous SNPs impair the drug uptake process of hOCT1, and hence patients with the former variants need tobe closely monitored for idiosyncratic adverse drug reactions or sub-therapeutic responses while being initiated intotherapy with hOCT1 substrates.
Description
Keywords
Organic cation transporter, non-synonymous, polymorphism, drug transport
Citation
Manvi Akash Ashok, Rodrigues Elmer Clover, Afreen Munazza, Padmapriyan Samuel Gideon George. Effect of 1022C>T and 1222A>G genetic polymorphisms of SLC22A1 gene on substrates binding to human organic cation transporter 1. Journal of Applied Pharmaceutical Science. 2020 Sep; 2020 Sep: 072-081