Expression of Organic Cation Transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) Is Affected by Genetic Factors and Cholestasis in Human Liver
Expression of Organic Cation Transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) Is Affected by Genetic Factors and Cholestasis in Human Liver
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DOI：
10.1002/hep.23103
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发表时间：
2009-10-01
期刊：
影响因子：
13.5
通讯作者：
Schaeffeler, Elke
中科院分区：
文献类型：
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作者：
Nies, Anne T.;Koepsell, Hermann;Schaeffeler, Elke
肝细胞的一个重要功能是生物转化和消除各种药物，其中许多是有机阳离子，由溶质载体家族22 （SLC22）的有机阳离子转运体（OCTs）吸收。由于OCT表达的个体间差异可能影响对二甲双胍等阳离子药物的反应，我们系统地研究了人类肝脏中OCT1/SLC22A1和OCT3/SLC22A3表达的遗传和非遗传因素。分析了150例白种人肝脏组织中OCT1和OCT3（信使RNA [mRNA]、蛋白）的表达情况。通过免疫荧光显微镜对肝oct进行定位。采用基质辅助激光解吸/电离飞行时间质谱法和全基因组单核苷酸多态性微阵列技术对SLC22A1-A3/OCT1-3基因簇中的92个变异进行了基因分型。用转染细胞比较重组人OCT1和OCT3对二甲双胍的转运。ommrna和蛋白表达分别变化113倍和83倍，OCT3 mRNA表达变化27倍。OCT1转录物水平平均比OCT3高15倍。我们将OCT3蛋白定位到肝细胞膜基底外侧，并鉴定二甲双胍为OCT3底物。OCT1和OCT3的表达与年龄和性别无关，但在诊断为胆汁淤积的肝供者中，OCT1和OCT3的表达显著降低(P
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 duster. Transport of metformin by recombinant human OCT1 and OCT3 was compared using transfected cells. OM 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