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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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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.
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expression of organic cation transporters oct1 slc22a1 and oct3 slc22a3 is affected by genetic factors and cholestasis in human liver
Hepatology, 2009Co-Authors: Anne T Nies, Hermann Koepsell, Ulrich M Zanger, Stefan Winter, Oliver Burk, Kathrin Klein, Reinhold Kerb, Dietrich Keppler, Matthias SchwabAbstract:An important function of hepatocytes is the biotransformation and elimination of various drugs, many of which are organic cations and are taken up by organic cation transporters (OCTs) of the solute carrier family 22 (SLC22). Because interindividual variability of OCT expression may affect response to cationic drugs such as metformin, we systematically investigated genetic and nongenetic factors of OCT1/SLC22A1 and OCT3/SLC22A3 expression in human liver. OCT1 and OCT3 expression (messenger RNA [mRNA], protein) was analyzed in liver tissue samples from 150 Caucasian subjects. Hepatic OCTs were localized by way of immunofluorescence microscopy. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and genome-wide single-nucleotide polymorphism microarray technology served to genotype 92 variants in the SLC22A1-A3/OCT1-3 gene cluster. Transport of metformin by recombinant human OCT1 and OCT3 was compared using transfected cells. OCT1 mRNA and protein expression varied 113- and 83-fold, respectively; OCT3 mRNA expression varied 27-fold. OCT1 transcript levels were on average 15-fold higher compared with OCT3. We localized the OCT3 protein to the basolateral hepatocyte membrane and identified metformin as an OCT3 substrate. OCT1 and OCT3 expression are independent of age and sex but were significantly reduced in liver donors diagnosed as cholestatic (P ≤ 0.01). Several haplotypes for OCT1 and OCT3 were identified. Multivariate analysis adjusted for multiple testing showed that only the OCT1-Arg61Cys variant (rs12208357) strongly correlated with decreased OCT1 protein expression (P < 0.0001), and four variants in OCT3 (rs2292334, rs2048327, rs1810126, rs3088442) were associated with reduced OCT3 mRNA levels (P = 0.03). Conclusion: We identified cholestasis and genetic variants as critical determinants for considerable interindividual variability of hepatic OCT1 and OCT3 expression. This indicates consequences for hepatic elimination of and response to OCT substrates such as metformin. (HEPATOLOGY 2009.)
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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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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expression of organic cation transporters oct1 slc22a1 and oct3 slc22a3 is affected by genetic factors and cholestasis in human liver
Hepatology, 2009Co-Authors: Anne T Nies, Hermann Koepsell, Ulrich M Zanger, Stefan Winter, Oliver Burk, Kathrin Klein, Reinhold Kerb, Dietrich Keppler, Matthias SchwabAbstract:An important function of hepatocytes is the biotransformation and elimination of various drugs, many of which are organic cations and are taken up by organic cation transporters (OCTs) of the solute carrier family 22 (SLC22). Because interindividual variability of OCT expression may affect response to cationic drugs such as metformin, we systematically investigated genetic and nongenetic factors of OCT1/SLC22A1 and OCT3/SLC22A3 expression in human liver. OCT1 and OCT3 expression (messenger RNA [mRNA], protein) was analyzed in liver tissue samples from 150 Caucasian subjects. Hepatic OCTs were localized by way of immunofluorescence microscopy. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and genome-wide single-nucleotide polymorphism microarray technology served to genotype 92 variants in the SLC22A1-A3/OCT1-3 gene cluster. Transport of metformin by recombinant human OCT1 and OCT3 was compared using transfected cells. OCT1 mRNA and protein expression varied 113- and 83-fold, respectively; OCT3 mRNA expression varied 27-fold. OCT1 transcript levels were on average 15-fold higher compared with OCT3. We localized the OCT3 protein to the basolateral hepatocyte membrane and identified metformin as an OCT3 substrate. OCT1 and OCT3 expression are independent of age and sex but were significantly reduced in liver donors diagnosed as cholestatic (P ≤ 0.01). Several haplotypes for OCT1 and OCT3 were identified. Multivariate analysis adjusted for multiple testing showed that only the OCT1-Arg61Cys variant (rs12208357) strongly correlated with decreased OCT1 protein expression (P < 0.0001), and four variants in OCT3 (rs2292334, rs2048327, rs1810126, rs3088442) were associated with reduced OCT3 mRNA levels (P = 0.03). Conclusion: We identified cholestasis and genetic variants as critical determinants for considerable interindividual variability of hepatic OCT1 and OCT3 expression. This indicates consequences for hepatic elimination of and response to OCT substrates such as metformin. (HEPATOLOGY 2009.)
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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.
Anne T Nies - 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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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.
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expression of organic cation transporters oct1 slc22a1 and oct3 slc22a3 is affected by genetic factors and cholestasis in human liver
Hepatology, 2009Co-Authors: Anne T Nies, Hermann Koepsell, Ulrich M Zanger, Stefan Winter, Oliver Burk, Kathrin Klein, Reinhold Kerb, Dietrich Keppler, Matthias SchwabAbstract:An important function of hepatocytes is the biotransformation and elimination of various drugs, many of which are organic cations and are taken up by organic cation transporters (OCTs) of the solute carrier family 22 (SLC22). Because interindividual variability of OCT expression may affect response to cationic drugs such as metformin, we systematically investigated genetic and nongenetic factors of OCT1/SLC22A1 and OCT3/SLC22A3 expression in human liver. OCT1 and OCT3 expression (messenger RNA [mRNA], protein) was analyzed in liver tissue samples from 150 Caucasian subjects. Hepatic OCTs were localized by way of immunofluorescence microscopy. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and genome-wide single-nucleotide polymorphism microarray technology served to genotype 92 variants in the SLC22A1-A3/OCT1-3 gene cluster. Transport of metformin by recombinant human OCT1 and OCT3 was compared using transfected cells. OCT1 mRNA and protein expression varied 113- and 83-fold, respectively; OCT3 mRNA expression varied 27-fold. OCT1 transcript levels were on average 15-fold higher compared with OCT3. We localized the OCT3 protein to the basolateral hepatocyte membrane and identified metformin as an OCT3 substrate. OCT1 and OCT3 expression are independent of age and sex but were significantly reduced in liver donors diagnosed as cholestatic (P ≤ 0.01). Several haplotypes for OCT1 and OCT3 were identified. Multivariate analysis adjusted for multiple testing showed that only the OCT1-Arg61Cys variant (rs12208357) strongly correlated with decreased OCT1 protein expression (P < 0.0001), and four variants in OCT3 (rs2292334, rs2048327, rs1810126, rs3088442) were associated with reduced OCT3 mRNA levels (P = 0.03). Conclusion: We identified cholestasis and genetic variants as critical determinants for considerable interindividual variability of hepatic OCT1 and OCT3 expression. This indicates consequences for hepatic elimination of and response to OCT substrates such as metformin. (HEPATOLOGY 2009.)
Lili Magyari - One of the best experts on this subject based on the ideXlab platform.
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Susceptibility to ulcerative colitis in Hungarian patients determined by gene-gene interactions
World Journal of Gastroenterology, 2014Co-Authors: Patricia Sarlos, Veronika Csongei, Lili Magyari, Luca Jaromi, Dalma Várszegi, Lajos Nagy, Béla MeleghAbstract:AIM: To study the inflammatory bowel disease-5 locus (IBD5) and interleukin-23 receptor (IL23R) gene variants in UC patients and test for gene-gene interaction. METHODS: The study population (n = 625) was comprised of 320 unrelated ulcerative colitis (UC) patients with Caucasian origin and 316 age- and gender-matched, healthy controls. Five variants in the IBD5 locus (IGR2198a_1 rs11739135, IGR2096a_1 rs12521868, IGR2230a_1 rs17622208, SLC22A4 rs1050152 and SLC22A5 rs2631367) and two of the IL23R gene (rs1004819, rs2201841) were analysed. PCR and restriction fragment length polymorphism methods were used for genotyping, the SLC22A4 rs1050152 genotypes were determined by direct sequencing. Interactions and specific genotype combinations of the seven variants were tested by binary logistic regression analysis. The IL23R genotypes were stratified by IBD5 genotypes for further interaction analyses. RESULTS: For the IL23R rs1004819 A allele we found significantly higher allele frequency (P = 0.032) in UC patients compared to control subjects. The SNP rs1004819 showed significant association with UC risk for carriers (P = 0.004, OR = 1.606; 95%CI: 1.160-2.223) and the SNP rs2201841 for homozygotes (P = 0.030, OR = 1.983; 95%CI: 1.069-3.678). Individually none of the IBD5 markers conferred risk to UC development. There was no evidence for statistical interaction either between IBD5 loci and IL23R genes using logistic regression analysis. After genotype stratification, we could detect a positive association on the background of rs1004819 A allele for SLC22A4 T, SLC22A5 C, IGR2198a_1 C or IGR2096a_1 T allele, the highest OR was calculated in the presence of SLC22A4 T allele (P = 0.005, OR = 2.015; 95%CI: 1.230-3.300). There was no association with UC for any combinations of rs1004819 and IGR2230a_1. The IL23R rs2201841 homozygous genotype and IBD5 carrier status together did not confer susceptibility for UC. CONCLUSION: The present study has shown that UC susceptibility genes are likely to act in a complex interactive manner similar to CD.
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possible role of selected igr and SLC22A4 slc22a5 loci in development of inflammatory bowel diseases
Orvosi Hetilap, 2009Co-Authors: Lilla Lakner, Veronika Csongei, Lili Magyari, Marta Varga, Pal Miheller, Patricia Sarlos, Peter Orosz, Zsolt Bari, Istvan Takacs, Luca JaromiAbstract:Az idiopathias kronikus gyulladasos belbetegseg kialakulasaban kornyezeti tenyezők, immunologiai es genetikai faktorok egyarant szerepet jatszanak. Az utobbi evekben a CARD15 gen mellett egyre tobb adat tamasztja ala mas genek, tobbek kozott az 5q31-33 regioban elhelyezkedő IBD5 locus (MIM#606348) szerepet. Egyes tanulmanyok ezen regioban az SLC22A4 gen C1672T szubsztituciojanak, illetve az SLC22A5 gen G-207C transzverziojanak egyuttes szerepet hangsulyozzak, kulonosen Crohn-betegseg kialakulasaban, mig mas szerzők uj minor hajlamosito tenyezőket azonositottak az IBD5 kromoszomaregioban, ezek az IGR-variansok. Celkitűzes: Az SLC22A4 C1672T es SLC22A5 G-207C mutaciok mellett az IGR2096a_1 (rs12521868) es az IGR2198a_1 (rs11739135) polimorfizmusok szerepenek vizsgalata gyulladasos belbetegseg kialakulasaban. Betegek es modszer: Vizsgalatunk soran 440 gyulladasos belbeteg (206 Crohn- es 234 colitis ulcerosas beteg), valamint 279 kontrollegyen periferias vermintajabol PCR-RFLP technikaval vegeztunk DNS-analiz...
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IGR2096a_1 T and IGR2198a_1 C alleles on IBD5 locus of chromosome 5q31 region confer risk for Crohn’s disease in Hungarian patients
International Journal of Colorectal Disease, 2009Co-Authors: Lilla Lakner, Veronika Csongei, Lili Magyari, Marta Varga, Patricia Sarlos, Peter Orosz, Luca Jaromi, Judit Bene, Enikő Sáfrány, Pal MihellerAbstract:Background and aims We investigated the possible association of IBD with C1672T of SLC22A4 and G-207C of SLC22A5 alleles, and with the novel IGR2096a_1 (rs12521868) and IGR2198a_1 (rs11739135) susceptibility loci, all located on IBD5 locus of chromosome 5q31. Materials and methods DNA of 217 Crohn’s disease, 252 ulcerative colitis, and 290 control patients were analyzed by polymerase chain reaction/restriction fragment length polymorphism methods. Results Neither the C1672T and G-207C alleles, nor the TC haplotype were found to be risk factors. By contrast, the minor allele frequencies of IGR2096a_1 T (47.2%) and IGR2198a_1 C (45.9%) were increased in Crohn’s disease compared with the controls (38.2% and 37.7%, respectively; p
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Susceptibility genetic variants in Hungarian morbus Crohn and ulcerative colitis patients
Orvosi Hetilap, 2009Co-Authors: Lili Magyari, Béla MeleghAbstract:Gyulladasos belbetegsegekre (Crohn-betegseg, colitis ulcerosa) hajlamosito genek vizsgalatat vegeztuk magyar populacioban, ezek a CARD15 gen R702W, G908R, 1007finsC variansai, az SLC22A4 gen C1672T es az SLC22A5 G-207C variansai, valamint az altaluk meghatarozott TC haplotipus, a CTLA4 gen A+49G elterese es az IL23R gen rs10889677 C/A, rs2201841 T/C, rs1884444 G/T variansai. Vizsgalataink soran 201 felnőtt Crohn-beteg, 241 felnőtt colitis ulcerosas, valamint 19 gyermek Crohn-beteget analizaltunk. Kontrollnak 235 felnőttől es 49 gyermektől vettunk vert. A genotipizalas soran PCR/RFLP modszert es direkt szekvenalast alkalmaztunk. Eredmenyeink alapjan kijelenthetjuk, hogy a CARD15 gen mutacioi kozul felnőttekben az 1007finsC, mig gyermekekben az 1007finsC es a G908R varians is hajlamosit Crohn-betegseg kialakulasara. Az SLC22A4 es SLC22A5 genek altal meghatarozott TC haplotipus eseten nem talaltunk szignifikans kulonbseget a betegcsoportok kontrollokkal valo osszevetese soran. A CTLA4 gen A+49G variansa nem ...
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Plasma carnitine ester profiles in Crohn's disease patients characterized for SLC22A4 C1672T and SLC22A5 G-207C genotypes.
British Journal of Nutrition, 2007Co-Authors: Judit Bene, Lili Magyari, Pal Miheller, Katalin Komlósi, Gábor Talián, Krisztina Horváth, Beáta Gasztonyi, Mária Figler, Gyula Mózsik, Zsolt TulassayAbstract:Crohn's disease (CD) is a chronic inflammatory bowel disorder caused by environmental and genetic factors. The purpose of this study was to analyse the possible influence of functional variants of genes of OCTN cation transporters on the carnitine ester profile of patients with CD. Genotyping for SLC22A4 1672C --> T, SLC22A5-207G --> C mutations and three common NOD2 variants (R702W, G908R and 1007finsC) were performed in 100 adult CD patients and in ninety-four healthy controls by direct sequencing. The carnitine ester profile was determined using ESI triple quadrupole tandem MS. Contrary to the NOD2/CARD15 mutations, none of the SLC variants showed increased prevalence in the CD group, the prevalence of TC haplotype did not differ between the patients and the controls. In the mixed group of CD patients the fasting propionyl- (0.243 (sem 0.008) v. 0.283 (sem 0.014) micromol/l), butyryl- (0.274 (sem 0.009) v. 0.301 (sem 0.013)) and isovalerylcarnitine (0.147 (sem 0.006) v. 0.185 (sem 0.009)) levels were decreased; while the level of octenoyl- (0.086 (sem 0.006) v. 0.069 (sem 0.005)), myristoleyl- (0.048 (sem 0.003) v. 0.037 (sem 0.003)), palmitoyl- (0.140 (sem 0.005) v. 0.122 (sem 0.004)) and oleylcarnitine (0.172 (sem 0.006) v. 0.156 (sem 0.008); P < 0.05 in all comparisons) were increased. After sorting the patients into SLC22A genotype-specific subgroups, no significant differences could be observed between them. The carnitine ester profile data suggest selective involvement of the carnitine esters in CD patients, probably due to their altered metabolism.
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Haplotype in the IBD5 region is associated with refractory Crohn’s disease in Slovenian patients and modulates expression of the SLC22A5 gene
Journal of Gastroenterology, 2011Co-Authors: Katja Repnik, Uroš PotočnikAbstract:The IBD5 locus (OMIM ID 606348) on chromosome 5 was suggested to be one of the most important genetic factors involved in the pathogenesis of inflammatory bowel diseases (IBDs). However the main contributor from this region is still unknown. We investigated the possible association of the IBD5 locus with IBD in Slovenian patients and correlation between disease-associated single nucleotide polymorphisms (SNPs) and quantitative gene expression (eQTL) of candidate genes from the IBD5 locus in peripheral blood lymphocytes and colon tissue biopsies from IBD patients. We genotyped SNPs from the IBD5 locus in 312 healthy controls and 632 IBD patients. We found statistically significant association of polymorphisms rs1050152 in gene SLC22A4 (p = 0.005, OR = 2.177, 95% CI = 1.270–3.526) and rs2631372 in gene SLC22A5 (p = 0.001, OR = 0.473, 95% CI = 0.307–0.731) and TC haplotype of both polymorphisms (p = 0.006, OR = 1,541, 95% CI = 1.130–2.100) with refractory Crohn’s disease (CD) in Slovenian patients who do not respond to standard therapy, including patients who develop fistulas. We found decreased expression of SLC22A4 and SLC22A5 genes in peripheral blood lymphocytes from IBD patients compared to control group and decreased expression of SLC22A5 gene in inflamed tissue biopsies compared to noninflamed colon (p = 0.009). We found lower expression of SLC22A5 gene in IBD patients with disease-susceptible genotypes for both disease-associated SNPs. Our data suggest that SNPs and haplotype in the IBD5 SLC22A4/SLC22A5 region contribute to the development of particularly refractory Crohn’s disease in the Slovenian population, and expression studies in blood lymphocytes and colon tissue biopsies and eQTL analysis suggest that SLC22A5 is the main gene in the IBD5 region contributing to the IBD pathogenesis.
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Haplotype in the IBD5 region is associated with refractory Crohn’s disease in Slovenian patients and modulates expression of the SLC22A5 gene
Journal of Gastroenterology, 2011Co-Authors: Katja Repnik, Uroš PotočnikAbstract:Background The IBD5 locus (OMIM ID 606348) on chromosome 5 was suggested to be one of the most important genetic factors involved in the pathogenesis of inflammatory bowel diseases (IBDs). However the main contributor from this region is still unknown. Methods We investigated the possible association of the IBD5 locus with IBD in Slovenian patients and correlation between disease-associated single nucleotide polymorphisms (SNPs) and quantitative gene expression (eQTL) of candidate genes from the IBD5 locus in peripheral blood lymphocytes and colon tissue biopsies from IBD patients. We genotyped SNPs from the IBD5 locus in 312 healthy controls and 632 IBD patients. Results We found statistically significant association of polymorphisms rs1050152 in gene SLC22A4 ( p = 0.005, OR = 2.177, 95% CI = 1.270–3.526) and rs2631372 in gene SLC22A5 ( p = 0.001, OR = 0.473, 95% CI = 0.307–0.731) and TC haplotype of both polymorphisms ( p = 0.006, OR = 1,541, 95% CI = 1.130–2.100) with refractory Crohn’s disease (CD) in Slovenian patients who do not respond to standard therapy, including patients who develop fistulas. We found decreased expression of SLC22A4 and SLC22A5 genes in peripheral blood lymphocytes from IBD patients compared to control group and decreased expression of SLC22A5 gene in inflamed tissue biopsies compared to noninflamed colon ( p = 0.009). We found lower expression of SLC22A5 gene in IBD patients with disease-susceptible genotypes for both disease-associated SNPs. Conclusions Our data suggest that SNPs and haplotype in the IBD5 SLC22A4/SLC22A5 region contribute to the development of particularly refractory Crohn’s disease in the Slovenian population, and expression studies in blood lymphocytes and colon tissue biopsies and eQTL analysis suggest that SLC22A5 is the main gene in the IBD5 region contributing to the IBD pathogenesis.