Identification and Functional Characterization of a New Human Kidney–Specific H+/Organic Cation Antiporter, Kidney-Specific Multidrug and Toxin Extrusion 2

Masuda, Satohiro; Takato, Tsuyoshi; Yonezawa, Atsushi; Tanihara, Yuko; Kishimoto, Koshiro; Katsura, Toshiya; Ogawa, Osamu; Inui, Ken Ichi

doi:10.1681/asn.2006030205

Cited by 334 publications

(266 citation statements)

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“…Construction of non-synonymous variants of MATE1 and MATE2-K MATE1 and MATE2-K cDNA were excised from MATE1/pcDNA3.1 and MATE2-K/pcDNA3.1, 10 and were subcloned into pcDNA3.1/nV5-DEST (Invitrogen, Carsbad, CA, USA) to yield nV5-MATE1 and nV5-MATE2-K. Nonsynonymous variants were constructed by the site-directed mutagenesis of nV5-MATE1 and nV5-MATE2-K, using a QuikChange II Site-Directed Mutagenesis Kit (Stratagene, La Jolla, CA, USA) with the primers listed in Table 2. The nucleotide sequences of these constructs were confirmed using a multicapillary DNA sequencer RISA384 system (Shimadzu).…”

Section: Identification Of Snps Of Mate1 and Mate2-k Genesmentioning

confidence: 99%

“…For example, multidrug resistance-associated protein 4 (MRP4) was demonstrated to be responsible for the renal elimination of antiviral drugs, 6 diuretics 7 and cephalosporin antibiotics. 8 Human orthologs of the multidrug and toxin extrusion (MATE) family, members of which confer multidrug resistance on bacteria, were identified most recently, 9,10 and named MATE1 (SLC47A1) and MATE2-K (SLC47A2). Both transporters are expressed mainly in the renal brush border membranes, and are able to transport tetraethylammonium (TEA) utilizing an oppositely directed H + gradient as a driving force, 11 indicating that MATE1 and MATE2-K are H + /organic cation antiporters.…”

Section: Introductionmentioning

confidence: 99%

“…[15][16][17] Metformin showed large interindividual variation in renal clearance, and a potential genetic contribution by the renal transporter was speculated. 18 Because metformin is also a superior substrate for MATE1 and MATE2-K, 10,19 polymorphisms of MATE1 and MATE2-K genes may be involved in the interindividual difference in the renal clearance. We have recently identified a single nucleotide polymorphism (SNP) in the promoter region of MATE1 (À32G4A), which causes a decrease in Sp1 binding and promoter activity of approximately 50%.…”

Section: Introductionmentioning

confidence: 99%

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Identification of multidrug and toxin extrusion (MATE1 and MATE2-K) variants with complete loss of transport activity

et al. 2009

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H + /organic cation antiporters (multidrug and toxin extrusion: MATE1 and MATE2-K) play important roles in the renal tubular secretion of cationic drugs. We have recently identified a regulatory single nucleotide polymorphism (SNP) of the MATE1 gene (À32G4A). There is no other information about SNPs of the MATE gene. In this study, we evaluated the functional significance of genetic polymorphisms in MATE1 and MATE2-K. We sequenced all exons of MATE1 and MATE2-K genes in 89 Japanese subjects and identified coding SNPs (cSNPs) encoding MATE1 (V10L, G64D, A310V, D328A and N474S) and MATE2-K (K64N and G211V). All the variants except for MATE1 V10L showed significant decrease in transport activity. In particular, MATE1 G64D and MATE2-K G211V variants completely lost transport activities. When membrane expression level was evaluated by cell surface biotinylation, those of MATE1 (G64D and D328A) and MATE2-K (K64N and G211V) were significantly decreased compared with that of wild type. These findings suggested that the loss of transport activities of the MATE1 G64D and MATE2-K G211V variants were due to the alteration of protein expression in cell surface membranes. This is the first demonstration of functional impairment of the MATE family induced by cSNPs.

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Section: Identification Of Snps Of Mate1 and Mate2-k Genesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification of multidrug and toxin extrusion (MATE1 and MATE2-K) variants with complete loss of transport activity

et al. 2009

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“…Thus, transporters appear to play important roles in the absorption, distribution and elimination of metformin. Many studies have shown that metformin is a substrate of various polyspecific organic cation transporters, which are important determinants of pharmacokinetics, including OCT1 (SLC22A1), OCT2 (SLC22A2), OCT3 (SLC22A3), MATE1 (SLC47A1), MATE2 (SLC47A2), PMAT (SLC29A4), and OCTN1 (SLC22A4) [11][12][13][14][15][16] (Fig. 1.1, Table 1).…”

Section: Introductionmentioning

confidence: 99%

Transporters Involved in Metformin Pharmacokinetics and Treatment Response

Liang

Giacomini

2017

Journal of Pharmaceutical Sciences

127

113

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Metformin, widely used as first-line treatment for type 2 diabetes, exists primarily as a hydrophilic cation at physiological pHs. As such, membrane transporters play a substantial role in its absorption, tissues distribution, and renal elimination. Multiple organic cation transporters are determinants of the pharmacokinetics of metformin, and many of them are important in its pharmacological action, as mediators of metformin entry into target tissues. Further, a recent genomewide association study (GWAS) in a large multi-ethnic population implicated polymorphisms in SLC2A2, encoding the glucose transporter, GLUT2, as important determinants of response to metformin. Here, we describe the key transporters associated with metformin pharmacokinetics and response.

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“…It was shown that OCT1-deficient mice had a much lower concentration of metformin in the liver compared with normal mice, indicating the importance of this transporter in the hepatic uptake of metformin [10]. OCT2 is involved in the renal excretion of metformin by controlling the basolateral transport of metformin from the blood into the tubular cells in the kidney [11], whereas the H + -drug antiporters multidrug and toxin extrusion 1 and 2 (MATE1 and MATE2) facilitate the extrusion of metformin into the urine at the apical side of the renal tubular cells [12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Intake ofStJohn's wort improves the glucose tolerance in healthy subjects who ingest metformin compared with metformin alone

Stage

Pedersen

Damkier

et al. 2015

Brit J Clinical Pharma

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AIMSOur objective was to investigate the steady-state pharmacokinetic and pharmacodynamic interaction between the antidepressive herbal medicine St John's wort and the antidiabetic drug metformin. METHODSWe performed an open cross-over study in 20 healthy male subjects, who received 1 g of metformin twice daily for 1 week with and without 21 days of preceding and concomitant treatment with St John's wort. The pharmacokinetics of metformin was determined, and a 2 h oral glucose tolerance test was performed. RESULTSSt John's wort decreased the renal clearance of metformin but did not affect any other metformin pharmacokinetic parameter. The addition of St John's wort decreased the area under the glucose concentration-time curve [702 (95% confidence interval, 643-761) vs. 629 min*mmol/L (95% confidence interval, 568-690), P = 0.003], and this effect was caused by a statistically significant increase in the acute insulin response. CONCLUSIONSSt John's wort improves glucose tolerance by enhancing insulin secretion independently of insulin sensitivity in healthy male subjects taking metformin. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT?• The pregnane X receptor agonist rifampicin lowers the plasma concentration of metformin and increases the glucose tolerance in healthy individuals.• It has not previously been investigated whether the herbal medicine St John's wort (SJW), which is also an agonist of the pregnane X receptor, exerts the same effect. WHAT THIS STUDY ADDS• There was no difference in the pharmacokinetics of metformin, except for a small albeit statistically significant reduction in renal clearance after treatment with SJW.• We show that SJW increases glucose tolerance in healthy subjects who ingest metformin.• The effect was caused by an increase in the acute insulin response.

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Identification and Functional Characterization of a New Human Kidney–Specific H+/Organic Cation Antiporter, Kidney-Specific Multidrug and Toxin Extrusion 2

Cited by 334 publications

References 25 publications

Identification of multidrug and toxin extrusion (MATE1 and MATE2-K) variants with complete loss of transport activity

Identification of multidrug and toxin extrusion (MATE1 and MATE2-K) variants with complete loss of transport activity

Transporters Involved in Metformin Pharmacokinetics and Treatment Response

Intake ofStJohn's wort improves the glucose tolerance in healthy subjects who ingest metformin compared with metformin alone

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