Interindividual variability of canalicular ATP-binding-cassette (ABC)-transporter expression in human liver
Interindividual variability of canalicular ATP-binding-cassette (ABC)-transporter expression in human liver
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DOI：
10.1002/hep.21214
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发表时间：
2006-07-01
期刊：
影响因子：
13.5
通讯作者：
Stieger, Bruno
中科院分区：
文献类型：
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作者：
Meier, Yvonne;Pauli-Magnus, Christiane;Stieger, Bruno
肝小管转运蛋白表达的个体差异性可能是肝脏疾病发展的易感因素，如获得性肝内胆汁淤积症。因此，我们研究了胆盐输出泵(BSEP，ABCB11)、多药耐药蛋白3(MDR3，ABCB4)、多药耐药相关蛋白2(MRP2，ABCC2)和多药耐药蛋白1(MDR1，ABCB1)在白人健康肝组织中的表达模式。蛋白表达水平与相应转运蛋白基因的特异性单核苷酸多态(SNPs)相关。110例肝切除患者的肝脏蛋白表达水平通过富含小管标记酶的肝细胞质膜的蛋白质印迹分析进行了评估。对每个个体进行了以下同义(S)和非同义(Ns)SNPs的基因分型：ABCB11：(NS：1457T>；C和2155A>；G)，ABCB4(NS：3826A>；G)和ABCC2(ns：1286G>；A，3600T>；A和4581G>；A)和ABCB1(ns：2677G>；T/A和S：3435C>；T)。转运蛋白的表达遵循单峰分布。然而，在所有受试者中，30%的人表现出至少四种转运蛋白中的一种的高表达，32%的人表现出低或极低的表达表型。转运蛋白的表达水平与年龄、性别、潜在的肝病或术前用药无关。然而，BSEP的低表达与ABCB11的1457C等位基因相关(P=.167)，而MRP2的高表达与ABCC2的3600A和4581AABCC2变异显著相关(P=0.006)。总而言之，研究结果显示出相当大的个体间差异。小管转运蛋白在正常肝脏中表达的变异性。此外，数据表明息肉形态转运体的表达模式，这可能构成一个危险因素的发展的获得性形式的胆汁淤积性肝病。
Interindividual variability in hepatic canalicular transporter expression might predispose to the development of hepatic disorders such as acquired forms of intrahepatic cholestasis. We therefore investigated expression patterns of bile salt export pump (BSEP, ABCB11), multidrug resistance protein 3 (MDR3, ABCB4), multidrug resistance associated protein 2 (MRP2, ABCC2) and multidrug resistance protein 1 (MDR1, ABCB1) in healthy liver tissue of a white population. Protein expression levels were correlated with specific single nucleotide polymorphisms (SNPs) in the corresponding transporter genes. Hepatic protein expression levels from 110 individuals undergoing liver resection were assessed by Western blot analysis of liver plasma membranes enriched in canalicular marker enzymes. Each individual was genotyped for the following synonymous (s) and nonsynonymous (ns) SNPs: ABCB11: (ns:1457T > C and 2155A > G),ABCB4.(ns:3826A > G) and ABCC2 (ns:1286G > A,3600T > A and 4581G > A) and ABCB1 (ns: 2677G > T/A and s:3435C > T). Transporter expression followed unimodal distribution. However, of all tested individuals 30% exhibited a high expression and 32% a low or very low expression phenotype for at least one of the four investigated transport proteins. Transporter expression levels did not correlate with age, sex, underlying liver disease, or presurgery medication. However, low BSEP expression was associated with the 1457C-allele inABCB11 (P =.167) and high MRP2 expression was significantly correlated with the 3600A and 4581A ABCC2 variants (P =.006). In conclusion, the results demonstrate a considerable interindividual. variability of canalicular transporter expression in normal liver. Furthermore, data suggest a polyp morphic transporter expression pattern, which might constitute a risk factor for the development of acquired forms of cholestatic liver diseases.