scholarly journals Stereoselective binding of chiral ligands to single nucleotide polymorphisms of the human organic cation transporter-1 determined using cellular membrane affinity chromatography

2010 ◽  
Vol 401 (1) ◽  
pp. 148-153 ◽  
Author(s):  
R. Moaddel ◽  
F. Bighi ◽  
R. Yamaguchi ◽  
S. Patel ◽  
S. Ravichandran ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Affinity Chromatography ◽  
Organic Cation ◽  
Organic Cation Transporter ◽  
Cellular Membrane ◽  
Chiral Ligands ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Membrane Affinity ◽  
Organic Cation Transporter 1

Fourteen Novel Single Nucleotide Polymorphisms in the SLC22A2 Gene Encoding Human Organic Cation Transporter (OCT2)

2004 ◽  
Vol 19 (3) ◽  
pp. 239-244 ◽  
Author(s):  
Hiromi fukushima-Uesaka ◽  
Keiko Maekawa ◽  
Shogo Ozawa ◽  
Kazuo Komamura ◽  
Kazuyuki Ueno ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Organic Cation ◽  
Organic Cation Transporter ◽  
Nucleotide Polymorphisms ◽  
Gene Encoding ◽  
Single Nucleotide

scholarly journals Single nucleotide polymorphisms in the intergenic region between metformin transporter OCT2 and OCT3 coding genes are associated with short-term response to metformin monotherapy in type 2 diabetes mellitus patients

2016 ◽  
Vol 175 (6) ◽  
pp. 531-540 ◽  
Author(s):  
Linda Zaharenko ◽  
Ineta Kalnina ◽  
Kristine Geldnere ◽  
Ilze Konrade ◽  
Solveiga Grinberga ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Single Nucleotide Polymorphisms ◽  
Pharmacokinetic Study ◽  
Organic Cation ◽  
Organic Cation Transporter ◽  
Nucleotide Polymorphisms ◽  
Short Term ◽  
Single Nucleotide ◽  
Flanking Region

Objective(s) High variability in clinical response to metformin is often observed in type 2 diabetes (T2D) patients, and it highlights the need for identification of genetic components affecting the efficiency of metformin therapy. Aim of this observational study is to evaluate the role of tagSNPs (tagging single nucleotide polymorphisms) from genomic regions coding for six metformin transporter genes with respect to the short-term efficiency. Design 102 tagSNPs in 6 genes coding for metformin transporters were genotyped in the group of 102 T2D patients treated with metformin for 3 months. Methods Most significant hits were analyzed in the group of 131 T2D patients from Slovakia. Pharmacokinetic study in 25 healthy nondiabetic volunteers was conducted to investigate the effects of identified polymorphisms. Results In the discovery group of 102 patients, minor alleles of rs3119309, rs7757336 and rs2481030 were significantly nominally associated with metformin inefficiency (P = 1.9 × 10−6 to 8.1 × 10−6). Effects of rs2481030 and rs7757336 did not replicate in the group of 131 T2DM patients from Slovakia alone, whereas rs7757336 was significantly associated with a reduced metformin response in combined group. In pharmacokinetic study, group of individuals harboring risk alleles of rs7757336 and rs2481030 displayed significantly reduced AUC∞ of metformin in plasma. Conclusions For the first time, we have identified an association between the lack of metformin response and SNPs rs3119309 and rs7757336 located in the 5′ flanking region of the genes coding for Organic cation transporter 2 and rs2481030 located in the 5′ flanking region of Organic cation transporter 3 that was supported by the results of a pharmacokinetic study on 25 healthy volunteers.

Human multidrug and toxin extrusion 1 (MATE1/SLC47A1) transporter: functional characterization, interaction with OCT2 (SLC22A2), and single nucleotide polymorphisms

2010 ◽  
Vol 298 (4) ◽  
pp. F997-F1005 ◽  
Author(s):  
Henriette E. Meyer zu Schwabedissen ◽  
Celine Verstuyft ◽  
Heyo K. Kroemer ◽  
Laurent Becquemont ◽  
Richard B. Kim
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Organic Cation ◽  
Expression System ◽  
Renal Elimination ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Transfected Cells ◽  
Cellular Accumulation ◽  
Renal Tubular Cells ◽  
Toxin Extrusion

renal elimination of a number of cationic compounds is thought to be mediated by the organic cation transporter 2 (OCT2, SLC22A2), a drug uptake transporter expressed at the basolateral domain of renal tubular cells. Recently, the key efflux transporter for the secretion organic cations was identified as an electroneutral H+/organic cation exchanger termed the multidrug and toxin extrusion (MATE)-type transporter 1 (MATE1, SLC47A1). The key goals of this study were to assess the interplay between the renal cationic transporters OCT2 and MATE1 and the functional assessment of genetic variation in human MATE1. First, the ability of various agents to interact with OCT2- or MATE1-mediated transport was determined using a recombinant vaccinia expression system. We were able to identify several drugs in clinical use with a divergent inhibitory capacity for these transporters. Subsequently, we further assessed the effect of those compounds on the cellular accumulation of shared substrates using OCT2 and MATE1 double-transfected cells. Consistent with data obtained using single transporter transfected cells, compounds that exhibited preferential inhibition of MATE1 such as rapamycin and mitoxantrone induced significant cellular accumulation of cationic substrates. We next assessed the functional relevance of MATE1 genetic polymorphisms. Significant loss of transport activity for metformin and tetraethylammonium was noted for two nonsynonymous single nucleotide polymorphisms (SNPs), c.404T>C (p.159T>M) and c.1012G>A (p.338V>A). The c.404T>C was only seen in Asian subjects with an allele frequency of 1%, and the c.1012G>A SNP was much more common, especially among those of African descent. In conclusion, we show that coordinate function of MATE1 with OCT2 likely contributes to the vectorial renal elimination of organic cationic drugs and that altered activity of MATE1, whether by drugs or polymorphisms, should be considered as an important determinant of renal cationic drug elimination.

scholarly journals The hOCT1 SNPs M420del and M408V alter imatinib uptake and M420del modifies clinical outcome in imatinib-treated chronic myeloid leukemia

Blood ◽  
2013 ◽  
Vol 121 (4) ◽  
pp. 628-637 ◽  
Author(s):  
Athina Giannoudis ◽  
Lihui Wang ◽  
Andrea L. Jorgensen ◽  
George Xinarianos ◽  
Andrea Davies ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Organic Cation Transporter ◽  
Published Data ◽  
Imatinib Treatment ◽  
Mrna Levels ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Organic Cation Transporter 1 ◽  
Prognostic Importance

Abstract Although the prognosis of chronic myeloid leukemia (CML) patients treated with imatinib is good, many fail to develop an optimal response or lose one. This heterogeneity could be attributed to the presence of human organic cation transporter-1 (hOCT1) single nucleotide polymorphisms (SNPs). In the present study, we analyzed the effect of 23 hOCT1 SNPs on imatinib treatment outcome in newly diagnosed CML patients using MassARRAY sequencing and pyrosequencing. The only SNP associated with outcome was M420del (rs35191146), with patients with the M420del demonstrating an increased probability of imatinib treatment failure. In CML cell lines transfected with M420del and/or M408V, M420del significantly decreased imatinib uptake, but this effect was countered if the M408V (rs628031) SNP was also present. A similar effect was seen for the uptake of the hOCT1 substrates TEA+ and ASP+. Finally, apparent hOCT1 mRNA levels were studied using both our earlier primers covering the M420del and another set that did not. Different mRNA expression was observed, explaining the disparity in published data on the prognostic importance of hOCT1 mRNA and highlighting the importance of avoiding common SNP sites in primer design. These data demonstrate that the common M420del SNP can modulate the outcome of imatinib treatment.

Development of a simple method for the determination of single nucleotide polymorphisms

2010 ◽  
Vol 34 (8) ◽  
pp. S75-S75
Author(s):  
Weifeng Zhu ◽  
Zhuoqi Liu ◽  
Daya Luo ◽  
Xinyao Wu ◽  
Fusheng Wan
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Nucleotide Polymorphisms ◽  
Simple Method ◽  
Single Nucleotide
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