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Genetic variants in multidrug and toxic compound extrusion-1, hMATE1, alter transport function

Abstract

hMATE1 (human multidrug and toxin compound extrusion-1; encoded by SLC47A1) is thought to have an important function in the renal and hepatic elimination of drugs, endogenous compounds and environmental toxins. The goals of this study were to identify genetic variants of hMATE1 and to determine their effects on hMATE1 transport function. We identified four synonymous and six nonsynonymous, coding region variants in DNA samples from 272 individuals (68 Caucasians, 68 African Americans, 68 Asian Americans and 68 Mexican Americans). The overall prevalence of hMATE1 nonsynonymous variants was relatively low with three singleton variants and three variants having allele frequencies 2% in a specific ethnic group. The nonsynonymous hMATE1 variants were constructed and stably transfected into HEK-293 cells. Uptake studies using four known hMATE1 substrates (paraquat, metformin, tetraethylammonium and oxaliplatin) were performed in cells transfected with hMATE1 reference or variants. We found that two singleton variants, G64D and V480M, produced a complete loss of function for all four tested substrates whereas three polymorphic variants (allele frequencies 2%), L125F, V338I and C497S, significantly altered the transport function in a substrate-dependent manner. Confocal microscopy studies were consistent with functional studies suggesting that the altered function of the variants was due to altered localization to the plasma membrane. These data suggest that nonsynonymous variants in hMATE1 may alter drug disposition and ultimately affect clinical drug response.

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Accession codes

Accessions

GenBank/EMBL/DDBJ

Abbreviations

hMATE1:

human MATE1

MATE:

multidrug and toxic compound extrusion

OCT1:

organic cation transporter 1

OCT2:

organic cation transporter 2

SLC:

solute carrier superfamily

SNP:

single nucleotide polymorphism

TEA:

tetraethylammonium

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Acknowledgements

This work was supported by National Institutes of Health grants GM61390 and GM74929, and a grant from NEDO, Tokyo. YC was supported by National Research Service Award T32 GM07546 from the National Institutes of Health. We acknowledge James E Shima for his helpful advice on this paper. We also thank Alexandra G Ianculescu for her technical support on GFP images.

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Correspondence to Kathleen M Giacomini.

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Chen, Y., Teranishi, K., Li, S. et al. Genetic variants in multidrug and toxic compound extrusion-1, hMATE1, alter transport function. Pharmacogenomics J 9, 127–136 (2009). https://doi.org/10.1038/tpj.2008.19

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