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


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.

Download full-text


Available from: Sook Wah Yee, Sep 05, 2014
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    Biochemical and Biophysical Research Communications 04/2013; 434(2). DOI:10.1016/j.bbrc.2013.03.072 · 2.30 Impact Factor
    • "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]. "
    [Show abstract] [Hide abstract]
    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.
    11/2012; 2012(9):473829. DOI:10.6064/2012/473829
  • Source
    • "For example, patients with certain genetic variants of MATE including MATE1 and MATE2 may have different susceptibility to PQ toxicity. Two variants of human MATE1 with no function and four with altered function have been reported.48,49 Three of them were polymorphic in a particular ethnic population with allele frequencies greater than 2%. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Multidrug and toxin extrusion 1 (MATE1/solute carrier 47A1) mediates cellular transport of a variety of structurally diverse compounds. Paraquat (PQ), which has been characterized in vitro as a MATE1 substrate, is a widely used herbicide and can cause severe toxicity to humans after exposure. However, the contribution of MATE1 to PQ disposition in vivo has not been determined. In the present study, we generated Mate1-deficient (Mate1-/-) mice and performed toxicokinetic analyses of PQ in Mate1-/- and wild-type (Mate1+/+) mice. After a single intravenous administration of PQ (50 mg/kg), Mate1-/- mice exhibited significantly higher plasma PQ concentrations than Mate1+/+ mice. The renal PQ concentration was markedly increased in Mate1-/- mice compared with Mate1+/+ mice. The subsequent nephrotoxicity of PQ were examined in these mice. Three days after intraperitoneal administration of PQ (20 mg/kg), the transcript levels of N-acetyl-β-D-glucosaminidase (Lcn2) and kidney injury molecule-1 (Kim-1) in the kidney were remarkably enhanced in the Mate1-/- mice. This was accompanied by apparent difference in renal histology between Mate1-/- and Mate1+/+ mice. In conclusion, we demonstrated that Mate1 is responsible for renal elimination of PQ in vivo and the deficiency of Mate1 function confers deteriorated kidney injury caused by PQ in mice.
    Molecular Pharmaceutics 12/2011; 8(6):2476-83. DOI:10.1021/mp200395f · 4.38 Impact Factor
Show more