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Hidetaka Kamimura - One of the best experts on this subject based on the ideXlab platform.
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characterization of human organic cation transporter 1 oct1 SLC22A1 and oct2 slc22a2 mediated transport of 1 2 methoxyethyl 2 methyl 4 9 dioxo 3 pyrazin 2 ylmethyl 4 9 dihydro 1h naphtho 2 3 d imidazolium bromide ym155 monobromide a novel small molec
Drug Metabolism and Disposition, 2010Co-Authors: Tsuyoshi Minematsu, Megumi Iwai, Takashi Usui, Kenichi Umehara, Hidetaka KamimuraAbstract:1-(2-Methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro-1 H -naphtho[2,3- d ]imidazolium bromide (YM155 monobromide) is a novel small-molecule survivin suppressant that induces the down-regulation of survivin and exhibits potent antitumor activity in nude mice bearing human hormone refractory prostate carcinoma cell line PC-3. Although YM155, which has a cationic moiety in its structure, is influxed into its pharmacologically effective site (cancer cells) and one of its eliminating organs (hepatocytes) in a transporter-mediated manner, the mechanism seems to be different between the two cell types. The other eliminating organ is the kidney. In this study, the transport of [ 14 C]YM155 was characterized by using human embryonic kidney 293 cells expressing organic cation transporter 1 (OCT1/SLC22A1), OCT2 (SLC22A2), and OCT3 (SLC22A3). YM155 inhibited the uptake of a typical substrate [ 3 H]1-methyl-4-phenylpyridinium via OCT1, OCT2, and OCT3 with IC 50 values of 23.8, 15.9, and 108 μM, respectively. The time- and saturable concentration-dependent uptake of [ 14 C]YM155 was observed in cells expressing OCT1 and OCT2 with K m values of 22.1 and 2.67 μM, respectively, but not in cells expressing OCT3. By taking into consideration the tissue distribution and localization of each transporter, these results suggest that, in humans, YM155 is taken up from the blood into hepatocytes and proximal tubular cells via OCT1 and OCT2, respectively. The comparison of the IC 50 values of OCT inhibitors and K m values for the uptake of YM155 into cells expressing OCTs with those into cancer cell lines indicated that transporter(s) other than OCT1 and OCT2 are involved in the uptake of YM155 into cancer cell lines.
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Characterization of human organic cation transporter 1 (OCT1/SLC22A1)- and OCT2 (SLC22A2)-mediated transport of 1-(2-methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)- 4,9-dihydro-1H-naphtho[2,3-d]imidazolium bromide (YM155 monobromide), a nove
Drug metabolism and disposition: the biological fate of chemicals, 2009Co-Authors: Tsuyoshi Minematsu, Megumi Iwai, Takashi Usui, Kenichi Umehara, Hidetaka KamimuraAbstract:1-(2-Methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro-1 H -naphtho[2,3- d ]imidazolium bromide (YM155 monobromide) is a novel small-molecule survivin suppressant that induces the down-regulation of survivin and exhibits potent antitumor activity in nude mice bearing human hormone refractory prostate carcinoma cell line PC-3. Although YM155, which has a cationic moiety in its structure, is influxed into its pharmacologically effective site (cancer cells) and one of its eliminating organs (hepatocytes) in a transporter-mediated manner, the mechanism seems to be different between the two cell types. The other eliminating organ is the kidney. In this study, the transport of [ 14 C]YM155 was characterized by using human embryonic kidney 293 cells expressing organic cation transporter 1 (OCT1/SLC22A1), OCT2 (SLC22A2), and OCT3 (SLC22A3). YM155 inhibited the uptake of a typical substrate [ 3 H]1-methyl-4-phenylpyridinium via OCT1, OCT2, and OCT3 with IC 50 values of 23.8, 15.9, and 108 μM, respectively. The time- and saturable concentration-dependent uptake of [ 14 C]YM155 was observed in cells expressing OCT1 and OCT2 with K m values of 22.1 and 2.67 μM, respectively, but not in cells expressing OCT3. By taking into consideration the tissue distribution and localization of each transporter, these results suggest that, in humans, YM155 is taken up from the blood into hepatocytes and proximal tubular cells via OCT1 and OCT2, respectively. The comparison of the IC 50 values of OCT inhibitors and K m values for the uptake of YM155 into cells expressing OCTs with those into cancer cell lines indicated that transporter(s) other than OCT1 and OCT2 are involved in the uptake of YM155 into cancer cell lines.
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carrier mediated uptake of 1 2 methoxyethyl 2 methyl 4 9 dioxo 3 pyrazin 2 ylmethyl 4 9 dihydro 1h naphtho 2 3 d imidazolium bromide ym155 monobromide a novel small molecule survivin suppressant into human solid tumor and lymphoma cells
Drug Metabolism and Disposition, 2009Co-Authors: Tsuyoshi Minematsu, Megumi Iwai, Kenji Sugimoto, Nobuaki Shirai, Takahito Nakahara, Takashi Usui, Hidetaka KamimuraAbstract:1-(2-Methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazolium bromide (YM155 monobromide) is a novel small-molecule survivin suppressant that induces the down-regulation of survivin and exhibits potent antitumor activity in nude mice bearing the human hormone refractory prostate carcinoma cell line PC-3. In this study, radioluminographic determination of the in vivo distribution of radioactivity after administration of [14C]YM155 to PC-3-xenografted nude mice revealed a relatively high level of radioactivity in the PC-3 xenograft. Therefore, the uptake of [14C]YM155 was further characterized in vitro using PC-3, lung cancer (Calu-6 and NCI-H358), malignant melanoma (A375 and SK-MEL-5), and non-Hodgkin9s lymphoma (RL and Ramos) cell lines. The uptake of [14C]YM155 in these cell lines was dependent on incubation time, temperature, and drug concentration. The Michaelis-Menten constant values were similar among the seven cell lines (0.189–0.367 μM). The effects of various compounds on the uptake of [14C]YM155 were tested in PC-3, Calu-6, A375, RL, and Ramos cell lines. Of the compounds tested, the cationic transporter substrates/inhibitors (tetraethylammonium, 1-methyl-4-phenylpyridium, cimetidine, prazosin, corticosterone, verapamil, amantadine, procainamide, and N-methylnicotinamide) inhibited the uptake of [14C]YM155 to a similar extent among the five cell lines. The half-maximal inhibitory concentration values (IC50) of several compounds for the uptake of [14C]YM155 into PC-3 differed from those reported in the literature for human organic cation transporter 1 (OCT1/SLC22A1), OCT2 (SLC22A2), and OCT3 (SLC22A3). To summarize, YM155 was taken up into cancer cells in a carrier-mediated manner and with a similar affinity among all the cancer cell lines tested. An influx transporter(s) may contribute to this process.
Matthias Schwab - One of the best experts on this subject based on the ideXlab platform.
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DNA methylation is associated with downregulation of the organic cation transporter OCT1 (SLC22A1) in human hepatocellular carcinoma
Genome Medicine, 2011Co-Authors: Elke Schaeffeler, Hermann Koepsell, Ulrich M Zanger, Claus Hellerbrand, Anne T Nies, Stefan Winter, Stephan Kruck, Ute Hofmann, Heiko Van Der Kuip, Matthias SchwabAbstract:Background Organic cation transporters (OCTs) determine not only physiological processes but are also involved in the cellular uptake of anticancer agents. Based on microarray analyses in hepatocellular carcinoma (HCC), SLC22A1 / OCT1 mRNA seems to be downregulated, but systematic protein expression data are currently missing. Moreover, the underlying molecular mechanisms responsible for altered SLC22A1 expression in HCC are not fully understood. Therefore, we investigated the role of DNA methylation in the transcriptional regulation of the family members SLC22A1 / OCT1, SLC22A2 / OCT2 and SLC22A3 / OCT3 in HCC. Methods Semiquantitative immunohistochemistry of SLC22A1 protein expression was performed in paired HCC and histological normal adjacent liver tissues ( n = 71) using tissue microarray analyses, and the results were correlated with clinicopathological features. DNA methylation, quantified by MALDI-TOF mass spectrometry and gene expression of SLC22A1, SLC22A2 and SLC22A3 were investigated using fresh-frozen HCC ( n = 22) and non-tumor adjacent liver tissues as well as histologically normal liver samples ( n = 120) from a large-scale liverbank. Results Based on tissue microarray analyses, we observed a significant downregulation of SLC22A1 protein expression in HCC compared to normal adjacent tissue ( P < 0.0001). SLC22A1 expression was significantly inverse correlated with expression of the proliferation marker MIB1/Ki-67 (r_s = -0.464, P < 0.0001). DNA methylation of SLC22A1 was significantly higher in HCC compared with non-tumor adjacent liver tissue and was lowest in histologically normal liver tissue. Methylation levels for SLC22A1 in combination with RASSF1A resulted in a specificity of > 90% and a sensitivity of 82% for discriminating HCC and tumor-free liver tissue. Conclusions DNA methylation of SLC22A1 is associated with downregulation of SLC22A1 in HCC and might be a new biomarker for HCC diagnosis and prognosis. Moreover, targeting SLC22A1 methylation by demethylating agents may offer a novel strategy for anticancer therapy of HCC.
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DNA methylation is associated with downregulation of the organic cation transporter OCT1 (SLC22A1) in human hepatocellular carcinoma.
Genome medicine, 2011Co-Authors: Elke Schaeffeler, Hermann Koepsell, Ulrich M Zanger, Claus Hellerbrand, Anne T Nies, Stefan Winter, Stephan Kruck, Ute Hofmann, Heiko Van Der Kuip, Matthias SchwabAbstract:Background Organic cation transporters (OCTs) determine not only physiological processes but are also involved in the cellular uptake of anticancer agents. Based on microarray analyses in hepatocellular carcinoma (HCC), SLC22A1/OCT1 mRNA seems to be downregulated, but systematic protein expression data are currently missing. Moreover, the underlying molecular mechanisms responsible for altered SLC22A1 expression in HCC are not fully understood. Therefore, we investigated the role of DNA methylation in the transcriptional regulation of the family members SLC22A1/OCT1, SLC22A2/OCT2 and SLC22A3/OCT3 in HCC.
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proton pump inhibitors inhibit metformin uptake by organic cation transporters octs
PLOS ONE, 2011Co-Authors: Elke Schaeffeler, Anne T Nies, Ute Hofmann, Claudia Resch, Maria Rius, Matthias SchwabAbstract:Metformin, an oral insulin-sensitizing drug, is actively transported into cells by organic cation transporters (OCT) 1, 2, and 3 (encoded by SLC22A1, SLC22A2, or SLC22A3), which are tissue specifically expressed at significant levels in various organs such as liver, muscle, and kidney. Because metformin does not undergo hepatic metabolism, drug-drug interaction by inhibition of OCT transporters may be important. So far, comprehensive data on the interaction of proton pump inhibitors (PPIs) with OCTs are missing although PPIs are frequently used in metformin-treated patients. Using in silico modeling and computational analyses, we derived pharmacophore models indicating that PPIs (i.e. omeprazole, pantoprazole, lansoprazole, rabeprazole, and tenatoprazole) are potent OCT inhibitors. We then established stably transfected cell lines expressing the human uptake transporters OCT1, OCT2, or OCT3 and tested whether these PPIs inhibit OCT-mediated metformin uptake in vitro. All tested PPIs significantly inhibited metformin uptake by OCT1, OCT2, and OCT3 in a concentration-dependent manner. Half-maximal inhibitory concentration values (IC50) were in the low micromolar range (3–36 µM) and thereby in the range of IC50 values of other potent OCT drug inhibitors. Finally, we tested whether the PPIs are also transported by OCTs, but did not identify PPIs as OCT substrates. In conclusion, PPIs are potent inhibitors of the OCT-mediated metformin transport in vitro. Further studies are needed to elucidate the clinical relevance of this drug-drug interaction with potential consequences on metformin disposition and/or efficacy.
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organic cation transporters octs mates in vitro and in vivo evidence for the importance in drug therapy
Handbook of experimental pharmacology, 2011Co-Authors: Anne T Nies, Hermann Koepsell, Katja Damme, Matthias SchwabAbstract:Organic cation transporters (OCTs) of the solute carrier family (SLC) 22 and multidrug and toxin extrusion (MATE) transporters of the SLC47 family have been identified as uptake and efflux transporters, respectively, for xenobiotics including several clinically used drugs such as the antidiabetic agent metformin, the antiviral agent lamivudine, and the anticancer drug oxaliplatin. Expression of human OCT1 (SLC22A1) and OCT2 (SLC22A2) is highly restricted to the liver and kidney, respectively. By contrast, OCT3 (SLC22A3) is more widely distributed. MATEs (SLC47A1, SLC47A2) are predominantly expressed in human kidney. Data on in vitro studies reporting a large number of substrates and inhibitors of OCTs and MATEs are systematically summarized. Several genetic variants of human OCTs and in part of MATE1 have been reported, and some of them result in reduced in vitro transport activity corroborating data from studies with knockout mice. A comprehensive overview is given on currently known genotype–phenotype correlations for variants in OCTs and MATE1 related to protein expression, pharmacokinetics/-dynamics of transporter substrates, treatment outcome, and disease susceptibility.
Tsuyoshi Minematsu - One of the best experts on this subject based on the ideXlab platform.
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characterization of human organic cation transporter 1 oct1 SLC22A1 and oct2 slc22a2 mediated transport of 1 2 methoxyethyl 2 methyl 4 9 dioxo 3 pyrazin 2 ylmethyl 4 9 dihydro 1h naphtho 2 3 d imidazolium bromide ym155 monobromide a novel small molec
Drug Metabolism and Disposition, 2010Co-Authors: Tsuyoshi Minematsu, Megumi Iwai, Takashi Usui, Kenichi Umehara, Hidetaka KamimuraAbstract:1-(2-Methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro-1 H -naphtho[2,3- d ]imidazolium bromide (YM155 monobromide) is a novel small-molecule survivin suppressant that induces the down-regulation of survivin and exhibits potent antitumor activity in nude mice bearing human hormone refractory prostate carcinoma cell line PC-3. Although YM155, which has a cationic moiety in its structure, is influxed into its pharmacologically effective site (cancer cells) and one of its eliminating organs (hepatocytes) in a transporter-mediated manner, the mechanism seems to be different between the two cell types. The other eliminating organ is the kidney. In this study, the transport of [ 14 C]YM155 was characterized by using human embryonic kidney 293 cells expressing organic cation transporter 1 (OCT1/SLC22A1), OCT2 (SLC22A2), and OCT3 (SLC22A3). YM155 inhibited the uptake of a typical substrate [ 3 H]1-methyl-4-phenylpyridinium via OCT1, OCT2, and OCT3 with IC 50 values of 23.8, 15.9, and 108 μM, respectively. The time- and saturable concentration-dependent uptake of [ 14 C]YM155 was observed in cells expressing OCT1 and OCT2 with K m values of 22.1 and 2.67 μM, respectively, but not in cells expressing OCT3. By taking into consideration the tissue distribution and localization of each transporter, these results suggest that, in humans, YM155 is taken up from the blood into hepatocytes and proximal tubular cells via OCT1 and OCT2, respectively. The comparison of the IC 50 values of OCT inhibitors and K m values for the uptake of YM155 into cells expressing OCTs with those into cancer cell lines indicated that transporter(s) other than OCT1 and OCT2 are involved in the uptake of YM155 into cancer cell lines.
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Characterization of human organic cation transporter 1 (OCT1/SLC22A1)- and OCT2 (SLC22A2)-mediated transport of 1-(2-methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)- 4,9-dihydro-1H-naphtho[2,3-d]imidazolium bromide (YM155 monobromide), a nove
Drug metabolism and disposition: the biological fate of chemicals, 2009Co-Authors: Tsuyoshi Minematsu, Megumi Iwai, Takashi Usui, Kenichi Umehara, Hidetaka KamimuraAbstract:1-(2-Methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro-1 H -naphtho[2,3- d ]imidazolium bromide (YM155 monobromide) is a novel small-molecule survivin suppressant that induces the down-regulation of survivin and exhibits potent antitumor activity in nude mice bearing human hormone refractory prostate carcinoma cell line PC-3. Although YM155, which has a cationic moiety in its structure, is influxed into its pharmacologically effective site (cancer cells) and one of its eliminating organs (hepatocytes) in a transporter-mediated manner, the mechanism seems to be different between the two cell types. The other eliminating organ is the kidney. In this study, the transport of [ 14 C]YM155 was characterized by using human embryonic kidney 293 cells expressing organic cation transporter 1 (OCT1/SLC22A1), OCT2 (SLC22A2), and OCT3 (SLC22A3). YM155 inhibited the uptake of a typical substrate [ 3 H]1-methyl-4-phenylpyridinium via OCT1, OCT2, and OCT3 with IC 50 values of 23.8, 15.9, and 108 μM, respectively. The time- and saturable concentration-dependent uptake of [ 14 C]YM155 was observed in cells expressing OCT1 and OCT2 with K m values of 22.1 and 2.67 μM, respectively, but not in cells expressing OCT3. By taking into consideration the tissue distribution and localization of each transporter, these results suggest that, in humans, YM155 is taken up from the blood into hepatocytes and proximal tubular cells via OCT1 and OCT2, respectively. The comparison of the IC 50 values of OCT inhibitors and K m values for the uptake of YM155 into cells expressing OCTs with those into cancer cell lines indicated that transporter(s) other than OCT1 and OCT2 are involved in the uptake of YM155 into cancer cell lines.
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carrier mediated uptake of 1 2 methoxyethyl 2 methyl 4 9 dioxo 3 pyrazin 2 ylmethyl 4 9 dihydro 1h naphtho 2 3 d imidazolium bromide ym155 monobromide a novel small molecule survivin suppressant into human solid tumor and lymphoma cells
Drug Metabolism and Disposition, 2009Co-Authors: Tsuyoshi Minematsu, Megumi Iwai, Kenji Sugimoto, Nobuaki Shirai, Takahito Nakahara, Takashi Usui, Hidetaka KamimuraAbstract:1-(2-Methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazolium bromide (YM155 monobromide) is a novel small-molecule survivin suppressant that induces the down-regulation of survivin and exhibits potent antitumor activity in nude mice bearing the human hormone refractory prostate carcinoma cell line PC-3. In this study, radioluminographic determination of the in vivo distribution of radioactivity after administration of [14C]YM155 to PC-3-xenografted nude mice revealed a relatively high level of radioactivity in the PC-3 xenograft. Therefore, the uptake of [14C]YM155 was further characterized in vitro using PC-3, lung cancer (Calu-6 and NCI-H358), malignant melanoma (A375 and SK-MEL-5), and non-Hodgkin9s lymphoma (RL and Ramos) cell lines. The uptake of [14C]YM155 in these cell lines was dependent on incubation time, temperature, and drug concentration. The Michaelis-Menten constant values were similar among the seven cell lines (0.189–0.367 μM). The effects of various compounds on the uptake of [14C]YM155 were tested in PC-3, Calu-6, A375, RL, and Ramos cell lines. Of the compounds tested, the cationic transporter substrates/inhibitors (tetraethylammonium, 1-methyl-4-phenylpyridium, cimetidine, prazosin, corticosterone, verapamil, amantadine, procainamide, and N-methylnicotinamide) inhibited the uptake of [14C]YM155 to a similar extent among the five cell lines. The half-maximal inhibitory concentration values (IC50) of several compounds for the uptake of [14C]YM155 into PC-3 differed from those reported in the literature for human organic cation transporter 1 (OCT1/SLC22A1), OCT2 (SLC22A2), and OCT3 (SLC22A3). To summarize, YM155 was taken up into cancer cells in a carrier-mediated manner and with a similar affinity among all the cancer cell lines tested. An influx transporter(s) may contribute to this process.
Hermann Koepsell - One of the best experts on this subject based on the ideXlab platform.
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Organic Anion and Cation Transporters in Renal Elimination of Drugs
Seldin and Giebisch's The Kidney, 2013Co-Authors: Gerhard Burckhardt, Hermann KoepsellAbstract:Renal proximal tubules efficiently secrete anionic and cationic drugs and toxins. Many of the involved transporters are members of the solute carrier family 22 ( SLC22 ) and exhibit a broad substrate specificity. Uptake of organic anions from blood into proximal tubule cells occurs through organic anion transporters 1 and 3 (OAT1/ SLC22A6 and OAT3/ SLC22A8 ), and the uptake of organic cations involves organic cation transporters 2 and 3 (OCT2/ SLC22A2 and OCT3/ SLC22A3 ). In humans, the release of organic anions from cells into the tubule lumen can occur by anion exchange (OAT4/ SLC22A9 ) and can be voltage- (NPT4/ SLC17A3 ) or ATP-driven (MRP2/ ABCC2 and MRP4/ ABCC4 ). Organic cations are released by exchange against protons through the multidrug and toxin extrusion 1 and 2-K (MATE1/ SLC47A1 and MATE2-K/ SLC47A2 ) and OCTN1/ SLC22A4 , by exchange against organic cations by OCT1 and OCTN2/ SLC22A5 , and by the ATP-driven P-glycoprotein (MDR1/ ABCB1 ). We summarize the molecular properties of the organic anion and cation transporters, their short and long term regulation and altered function as a consequence of single nucleotide polymorphisms, and their interaction with drugs.
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DNA methylation is associated with downregulation of the organic cation transporter OCT1 (SLC22A1) in human hepatocellular carcinoma
Genome Medicine, 2011Co-Authors: Elke Schaeffeler, Hermann Koepsell, Ulrich M Zanger, Claus Hellerbrand, Anne T Nies, Stefan Winter, Stephan Kruck, Ute Hofmann, Heiko Van Der Kuip, Matthias SchwabAbstract:Background Organic cation transporters (OCTs) determine not only physiological processes but are also involved in the cellular uptake of anticancer agents. Based on microarray analyses in hepatocellular carcinoma (HCC), SLC22A1 / OCT1 mRNA seems to be downregulated, but systematic protein expression data are currently missing. Moreover, the underlying molecular mechanisms responsible for altered SLC22A1 expression in HCC are not fully understood. Therefore, we investigated the role of DNA methylation in the transcriptional regulation of the family members SLC22A1 / OCT1, SLC22A2 / OCT2 and SLC22A3 / OCT3 in HCC. Methods Semiquantitative immunohistochemistry of SLC22A1 protein expression was performed in paired HCC and histological normal adjacent liver tissues ( n = 71) using tissue microarray analyses, and the results were correlated with clinicopathological features. DNA methylation, quantified by MALDI-TOF mass spectrometry and gene expression of SLC22A1, SLC22A2 and SLC22A3 were investigated using fresh-frozen HCC ( n = 22) and non-tumor adjacent liver tissues as well as histologically normal liver samples ( n = 120) from a large-scale liverbank. Results Based on tissue microarray analyses, we observed a significant downregulation of SLC22A1 protein expression in HCC compared to normal adjacent tissue ( P < 0.0001). SLC22A1 expression was significantly inverse correlated with expression of the proliferation marker MIB1/Ki-67 (r_s = -0.464, P < 0.0001). DNA methylation of SLC22A1 was significantly higher in HCC compared with non-tumor adjacent liver tissue and was lowest in histologically normal liver tissue. Methylation levels for SLC22A1 in combination with RASSF1A resulted in a specificity of > 90% and a sensitivity of 82% for discriminating HCC and tumor-free liver tissue. Conclusions DNA methylation of SLC22A1 is associated with downregulation of SLC22A1 in HCC and might be a new biomarker for HCC diagnosis and prognosis. Moreover, targeting SLC22A1 methylation by demethylating agents may offer a novel strategy for anticancer therapy of HCC.
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DNA methylation is associated with downregulation of the organic cation transporter OCT1 (SLC22A1) in human hepatocellular carcinoma.
Genome medicine, 2011Co-Authors: Elke Schaeffeler, Hermann Koepsell, Ulrich M Zanger, Claus Hellerbrand, Anne T Nies, Stefan Winter, Stephan Kruck, Ute Hofmann, Heiko Van Der Kuip, Matthias SchwabAbstract:Background Organic cation transporters (OCTs) determine not only physiological processes but are also involved in the cellular uptake of anticancer agents. Based on microarray analyses in hepatocellular carcinoma (HCC), SLC22A1/OCT1 mRNA seems to be downregulated, but systematic protein expression data are currently missing. Moreover, the underlying molecular mechanisms responsible for altered SLC22A1 expression in HCC are not fully understood. Therefore, we investigated the role of DNA methylation in the transcriptional regulation of the family members SLC22A1/OCT1, SLC22A2/OCT2 and SLC22A3/OCT3 in HCC.
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organic cation transporters octs mates in vitro and in vivo evidence for the importance in drug therapy
Handbook of experimental pharmacology, 2011Co-Authors: Anne T Nies, Hermann Koepsell, Katja Damme, Matthias SchwabAbstract:Organic cation transporters (OCTs) of the solute carrier family (SLC) 22 and multidrug and toxin extrusion (MATE) transporters of the SLC47 family have been identified as uptake and efflux transporters, respectively, for xenobiotics including several clinically used drugs such as the antidiabetic agent metformin, the antiviral agent lamivudine, and the anticancer drug oxaliplatin. Expression of human OCT1 (SLC22A1) and OCT2 (SLC22A2) is highly restricted to the liver and kidney, respectively. By contrast, OCT3 (SLC22A3) is more widely distributed. MATEs (SLC47A1, SLC47A2) are predominantly expressed in human kidney. Data on in vitro studies reporting a large number of substrates and inhibitors of OCTs and MATEs are systematically summarized. Several genetic variants of human OCTs and in part of MATE1 have been reported, and some of them result in reduced in vitro transport activity corroborating data from studies with knockout mice. A comprehensive overview is given on currently known genotype–phenotype correlations for variants in OCTs and MATE1 related to protein expression, pharmacokinetics/-dynamics of transporter substrates, treatment outcome, and disease susceptibility.
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Polyspecific Organic Cation Transporters: Structure, Function, Physiological Roles, and Biopharmaceutical Implications
Pharmaceutical Research, 2007Co-Authors: Hermann Koepsell, Katrin Lips, Christopher VolkAbstract:The body is equipped with broad-specificity transporters for the excretion and distribution of endogeneous organic cations and for the uptake, elimination and distribution of cationic drugs, toxins and environmental waste products. This group of transporters consists of the electrogenic cation transporters OCT1-3 ( SLC22A1-3 ), the cation and carnitine transporters OCTN1 ( SLC22A4 ), OCTN2 ( SLC22A5 ) and OCT6 ( SLC22A16 ), and the proton/cation antiporters MATE1, MATE2-K and MATE2-B. The transporters show broadly overlapping sites of expression in many tissues such as small intestine, liver, kidney, heart, skeletal muscle, placenta, lung, brain, cells of the immune system, and tumors. In epithelial cells they may be located in the basolateral or luminal membranes. Transcellular cation movement in small intestine, kidney and liver is mediated by the combined action of electrogenic OCT-type uptake systems and MATE-type efflux transporters that operate as cation/proton antiporters. Recent data showed that OCT-type transporters participate in the regulation of extracellular concentrations of neurotransmitters in brain, mediate the release of acetylcholine in non-neuronal cholinergic reactions, and are critically involved in the regulation of histamine release from basophils. The recent identification of polymorphisms in human OCTs and OCTNs allows the identification of patients with an increased risk for adverse drug reactions. Transport studies with expressed OCTs will help to optimize pharmacokinetics during development of new drugs.
Yinke Yang - One of the best experts on this subject based on the ideXlab platform.
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relationship between SLC22A1 and slc22a4 gene polymorphisms and risk of type 2 diabetes in chinese han population
Clinical Laboratory, 2018Co-Authors: Guanghui Long, Guangtao Zhang, Fangting Zhang, Dengke Yang, Yinke YangAbstract:Objective: This study was conducted to investigate the relationship between SLC22A1 and SLC22A4 gene polymorphisms and genetic susceptibility to type 2 diabetes in Chinese Han population. Methods: The research group comprised 110 patients with type 2 diabetes in Chinese Han population, while and the control group consisted of 110 healthy volunteers. The polymorphisms of SLC22A1 gene rs628031 and rs2282143 loci and SLC22A4 gene rs2073838 and rs272893 loci were detected in the subjects in the two groups. Genotype distributions and allele frequencies of the two genes were compared between the research and control groups. Results: Statistically significant differences were identified in the genotype distributions of SLC22A1 gene rs628031 and rs2282143 loci between the research and control groups (P SLC22A1 gene rs628031 locus and the T allele frequency of rs2282143 locus were higher in the research group than in the control group; these differences were statistically significant (P SLC22A4 gene rs2073838 locus exhibited no significant difference between the research and control groups (P>0.05). However, the genotype distributions of rs272893 locus showed a significant difference between the research and control groups (P<0.05). Conclusion: The polymorphisms of SLC22A1 gene rs628031 and rs2282143 loci and SLC22A4 gene rs272893 locus of patients with type 2 diabetes indicated a significant difference between the research and control groups, thereby suggesting that these genetic locus mutations increase the risk in patients with type 2 diabetes in Chinese Han population.
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Relationship Between SLC22A1 and SLC22A4 Gene Polymorphisms and Risk of Type 2 Diabetes in Chinese Han Population.
Clinical laboratory, 2018Co-Authors: Guanghui Long, Guangtao Zhang, Fangting Zhang, Dengke Yang, Yinke YangAbstract:Objective: This study was conducted to investigate the relationship between SLC22A1 and SLC22A4 gene polymorphisms and genetic susceptibility to type 2 diabetes in Chinese Han population. Methods: The research group comprised 110 patients with type 2 diabetes in Chinese Han population, while and the control group consisted of 110 healthy volunteers. The polymorphisms of SLC22A1 gene rs628031 and rs2282143 loci and SLC22A4 gene rs2073838 and rs272893 loci were detected in the subjects in the two groups. Genotype distributions and allele frequencies of the two genes were compared between the research and control groups. Results: Statistically significant differences were identified in the genotype distributions of SLC22A1 gene rs628031 and rs2282143 loci between the research and control groups (P SLC22A1 gene rs628031 locus and the T allele frequency of rs2282143 locus were higher in the research group than in the control group; these differences were statistically significant (P SLC22A4 gene rs2073838 locus exhibited no significant difference between the research and control groups (P>0.05). However, the genotype distributions of rs272893 locus showed a significant difference between the research and control groups (P
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retracted relationship between SLC22A1 and slc22a4 gene polymorphisms and risks of type 2 diabetes in chinese han population
Biomedical Research-tokyo, 2018Co-Authors: Guanghui Long, Guangtao Zhang, Fangting Zhang, Dengke Yang, Yinke YangAbstract:Objective: This study was conducted to investigate the relationship between SLC22A1 and SLC22A4 gene polymorphisms and genetic susceptibility to type 2 diabetes in Chinese Han population. Methods: The research group comprised 110 patients with type 2 diabetes in Chinese Han population, while and the control group consisted of 110 healthy volunteers. The polymorphisms of SLC22A1 gene rs628031 and rs2282143 loci and SLC22A4 gene rs2073838 and rs272893 loci were detected in the subjects in the two groups. Genotype distributions and allele frequencies of the two genes were compared between the research and control groups. Results: Statistically significant differences were identified in the genotype distributions of SLC22A1 gene rs628031 and rs2282143 loci between the research and control groups (P 0.05). However, the genotype distributions of rs272893 locus showed a significant difference between the research and control groups (P<0.05). Conclusion: The polymorphisms of SLC22A1 gene rs628031 and rs2282143 loci and SLC22A4 gene rs272893 locus of patients with type 2 diabetes indicated a significant difference between the research and control groups, thereby suggesting that these genetic locus mutations increase the risk in patients with type 2 diabetes in Chinese Han population.
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Retracted: Relationship between SLC22A1 and SLC22A4 gene polymorphisms and risks of type 2 diabetes in Chinese Han population
Biomedical Research, 2018Co-Authors: Guanghui Long, Guangtao Zhang, Fangting Zhang, Dengke Yang, Yinke YangAbstract:Objective: This study was conducted to investigate the relationship between SLC22A1 and SLC22A4 gene polymorphisms and genetic susceptibility to type 2 diabetes in Chinese Han population. Methods: The research group comprised 110 patients with type 2 diabetes in Chinese Han population, while and the control group consisted of 110 healthy volunteers. The polymorphisms of SLC22A1 gene rs628031 and rs2282143 loci and SLC22A4 gene rs2073838 and rs272893 loci were detected in the subjects in the two groups. Genotype distributions and allele frequencies of the two genes were compared between the research and control groups. Results: Statistically significant differences were identified in the genotype distributions of SLC22A1 gene rs628031 and rs2282143 loci between the research and control groups (P 0.05). However, the genotype distributions of rs272893 locus showed a significant difference between the research and control groups (P
