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Effect of 1022C>T and 1222A>G genetic polymorphisms of SLC22A1 gene on substrates binding to human organic cation transporter 1

Akash Ashok Manvi, Elmer Clover Rodrigues, Munazza Afreen, Samuel Gideon George Padmapriyan.


Human organic cation transporter 1 (hOCT1) is a transmembrane influx transporter protein encoded by the SLC22A1 gene. hOCT1 plays a pivotal role in the hepatocellular and renal uptake of several xenobiotics and endogenous substrates. 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 and substrate binding. The three-dimensional (3D) structures of hOCT1 variants were ab initio models using the iTASSER server, and drug-binding residues of the transmembrane domain were predicted using the Prankweb server. Substrate binding was analyzed by molecular docking using AutoDock 4.2.6. Amino acid residues, crucial for substrate binding and transport, were altered in Met408Val and Pro341Leu variants and were suggestive of conformational change induced by 1022C>T and 1222A>G SNPs. Moreover, a statistically significant difference was observed between the binding affinities of substrates to wild and mutant variants. Therefore, it is evident that 1022C>T and 1222A>G non-synonymous SNPs impair the drug uptake process of hOCT1, and hence patients with the former variants need to be closely monitored for idiosyncratic adverse drug reactions or sub-therapeutic responses while being initiated into therapy with hOCT1 substrates.

Key words: Organic Cation Transporter, Non-synonymous, Polymorphism, Drug transport

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