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

Division of Clinical Pharmacology and Experimental Therapeutics, Department of Biopharmaceutical Sciences, University of California at San Francisco, San Francisco, CA 94158, USA.
The Pharmacogenomics Journal (Impact Factor: 4.23). 02/2009; 9(2):127-36. DOI: 10.1038/tpj.2008.19
Source: PubMed

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 > or =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 > or =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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Available from: Sook Wah Yee, Sep 05, 2014
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    • "Several groups identified genetic variants in the promoter and exons of the SLC47A1 gene (Kajiwara et al., 2007, 2009; Chen et al., 2009; Ha Choi et al., 2009; Meyer zu Schwabedissen et al., 2010). Two single nucleotide polymorphisms (SNPs) in the 59-untranslated promoter region were recognized as functional SNPs that regulate the transcriptional activity of SLC47A1, and some nonsynonymous SNPs in the coding region have been functionally characterized (Chen et al., 2009; Kajiwara et al., 2009; Meyer zu Schwabedissen et al., 2010). Furthermore, the genetic variant in the promoter significantly reduced the renal clearance of metformin-selected substrate of MATE1 (Christensen et al., 2013). "
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    ABSTRACT: This study was performed to identify genetic polymorphisms in multidrug and toxin extrusion 2-K (MATE2-K, SLC47A2), a proton/organic cation antiporter that plays a role in the transport of organic cations across the apical membrane in kidney epithelial cells into the urine, and to demonstrate their effects on MATE2-K functions in vitro. Four of the thirty single nucleotide polymorphisms (SNPs) we identified in three ethnic groups (Caucasian, African American, and Japanese) were novel [308C>G (P103R), c.487-8C>T, 818A>G (Y273C), and c.1018+14T>C]. The transport activities of the prototypical substrates, tetraethylammonium and metformin, for four nonsynonymous SNPs (P103R, P162L, G211V, and Y273C) were significantly different from those of the wild type. In particular, transport activity was higher in P103R than in the wild type, which is the first time elevated transport activity was demonstrated due to these coding SNPs. Kinetic analysis revealed that P103R had a higher Vmax value, while Y273C had a lower value than that in the wild type. Cell surface protein expression levels were higher for P103R than for the wild type, whereas Y273C expression was decreased. Immunofluorescence analysis revealed that the P103R protein was localized to the plasma membrane, whereas Y273C showed cytoplasmic localization. Therefore, the difference in transport activities between P103R and Y273C variants was suggested to be responsible for the different protein expression levels observed at the plasma membrane. Four nonsynonymous SNPs in this study showed relatively low allelic frequencies (0.5 to 2.1%), but these were associated with markedly reduced or increased MATE2-K function.
    Preview · Article · Jul 2014 · Drug metabolism and disposition: the biological fate of chemicals
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    • "Choi et al. [5] have focused on the basal promote r region of MATE1 in ethnicall y diverse US populations, whereas other studies have reported several nonsynonym ous variants of MATE1 that showed significant changes in transport activities [4] [7]. In this study, we screened the coding and wide ranges (up to À2000 bp from the translationa l start site) of the promoter region of MATE1 in 48 samples from healthy Koreans and found two previously reported nonsynony mous variants, p.D64G and p.L125F [4] [7], and five promoter variants including three that are novel. Using luciferase assays, we found one common MATE1 promote r haplotype containing one variant, g.À1975C>A, that showed a significant increase in reporter activity. "
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    ABSTRACT: Multidrug and toxin extrusion 1 (MATE1, SLC47A1), an organic cation transporter, plays an important role in the renal and biliary elimination of various clinical drugs, including the anti-diabetic drug metformin. The goal of this study was to identify and characterize novel genetic variants of MATE1. Five variants in the promoter region and two nonsynonymous variants, p.D64G and p.L125F, were identified in 48 DNA samples from healthy Koreans. MATE1 promoter haplotype 3 containing g.-1975C>A showed a significant increase in reporter activity. Three transcription factors, Nkx-2.5, SREBP-1, and USF-1 were predicted to bind to the promoter in the region of g.-1975C>A. Results from electrophoretic mobility shift assays showed that the g.-1975A allele exhibits greater binding affinity to all of these transcription factors than the g.-1975C allele. In particular, we found that Nkx-2.5 and USF-1 induce MATE1 transcription. Our study suggests that the common promoter haplotype of MATE1 changes MATE1 transcriptional activity regulated by Nkx-2.5, SREBP-1, and USF-1.
    Preview · Article · Apr 2013 · Biochemical and Biophysical Research Communications
    • "In the SLC47A1 and SLC47A2 genes, 11 and 2 nonsynonymous SNPs, respectively, were found, some of which affected the transporter function. The mutations G64D and V480 M in MATE1 and G211V in MATE2-K caused a complete loss of function [191, 192], in this way affecting the pharmacokinetics of all substrates. In addition, polymorphisms in the promoter region of MATE1 with effects on binding and transcription activity of transcription factors were identified [193]. "
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    ABSTRACT: Transporters are important mediators of specific cellular uptake and thus, not only for effects, but also for side effects, metabolism, and excretion of many drugs such as cisplatin. Cisplatin is a potent cytostatic drug, whose use is limited by its severe acute and chronic nephro-, oto-, and peripheral neurotoxicity. For this reason, other platinum derivatives, such as carboplatin and oxaliplatin, with less toxicity but still with antitumoral action have been developed. Several transporters, which are expressed on the cell membranes, have been associated with cisplatin transport across the plasma membrane and across the cell: the copper transporter 1 (Ctr1), the copper transporter 2 (Ctr2), the P-type copper-transporting ATPases ATP7A and ATP7B, the organic cation transporter 2 (OCT2), and the multidrug extrusion transporter 1 (MATE1). Some of these transporters are also able to accept other platinum derivatives as substrate. Since membrane transporters display a specific tissue distribution, they can be important molecules that mediate the entry of platinum derivatives in target and also nontarget cells possibly mediating specific effects and side effects of the chemotherapeutic drug. This paper summarizes the literature on toxicities of cisplatin compared to that of carboplatin and oxaliplatin and the interaction of these platinum derivatives with membrane transporters.
    No preview · Article · Nov 2012
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