3种跨膜转运蛋白在胆管细胞损伤型药物性肝损伤患者肝组织中的表达特点及意义

叶立红; 郑欢伟; 黄肖雨; 郭立杰; 张海丛; 刘志权; 王翀奎

doi:10.3969/j.issn.1001-5256.2020.07.022

3种跨膜转运蛋白在胆管细胞损伤型药物性肝损伤患者肝组织中的表达特点及意义

DOI: 10.3969/j.issn.1001-5256.2020.07.022

1. 石家庄市第五医院病理科
2. 石家庄市第五医院肝病中心
3. 石家庄市第五医院药剂科
4. 河北中医学院实验中心

基金项目:

中国肝炎防治基金会-天晴肝病研究基金课题(TQGB20200047)；

详细信息

中图分类号: R575
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出版历程
- 出版日期: 2020-07-20

Expression characteristics and significance of three transmembrane transport proteins in liver tissue in bile duct injury type of drug-induced liver injury

1. 2.3 a. Department of Pathology, b. Liver Research Center, c. Department of Pharmacy, The Fifth Hospital of Shijiazhuang, Shijiazhuang 050021, China;
4. Experimental Center, Hebei University of Chinese Medicine, Shijiazhuang 050200, China

Research funding:

摘要

摘要:
目的探讨ABCB11（胆汁酸盐输出泵,BSEP）、ABCC2（多药耐药相关蛋白2,MRP2）和ABCB4（多药耐药糖蛋白3,MDR3）在胆管细胞损伤型药物性肝损伤（DILI）肝组织中的表达特点及意义。方法收集收集2010年1月-2017年6月石家庄市第五医院有明确用药史、经肝穿组织病理诊断为胆管细胞损伤型DILI的112例患者的临床资料,分为混合性肝炎组（混合组,n=40）、胆汁淤积性肝炎组（胆汁淤积组,n=40）及单纯性胆汁淤积组（单纯组,n=32）,同时选取20例无胆汁淤积的HBV携带者作为对照组。对所有入选病例肝穿组织进行BSEP、MDR3、MRP2免疫组化标记,观察三者的阳性表达特点及与病理形态学改变之间的关系,对比三亚型组间3种转运蛋白的表达差异,并分析3种转运蛋白表达与TBil、DBil、ALP、GGT、TBA之间的相关性。计量资料多组间比较采用单因素方差分析,进一步两两比较采用LSD-t检验;相关性分析采用Pearson相关分析。结果与对照组比较,BSEP、MDR3、MRP2在混合组、胆汁淤积组和单纯组肝组织中均表现为阳性表达减少（F值分别为48. 765、45. 424...
- 化学性与药物性肝损伤 /
- 载体蛋白质类 /
- 免疫组织化学
Abstract:
Objective To investigate the expression characteristics and significance of ABCB11( bile salt export pump,BSEP),ABCC2( multidrug resistant protein 2,MRP2),and ABCB4( multidrug resistance associated protein 3,MDR3) in the liver tissue in bile duct injury type of drug-induced liver injury( DILI). Methods Clinical data were collected from 112 patients who had a definite history of medication and were diagnosed with bile duct injury type of DILI based on liver biopsy in The Fifth Hospital of Shijiazhuang from January 2010 to June 2017. The patients were divided into mixed hepatitis group with 40 patients,cholestatic hepatitis group with 40 patients,and simple cholestasis group with 32 patients,and 20 hepatitis B virus carriers without cholestasis were enrolled as control group. Liver biopsy was performed for all subjects to perform immunohistochemical staining of BSEP,MDR3,and MRP2,and the expression characteristics of the three proteins and their association with pathomorphological changes were observed. The expression of these three transport proteins was compared between the three subtypes and its correlation with total bilirubin( TBil),direct bilirubin( DBil),alkaline phosphatase,gamma-glutamyl transpeptidase,and total bile acid( TBA) was analyzed. A one-way analysis of variance was used for comparison of continuous data between groups,and the least significant difference t-test was used for further comparison between two groups; a Pearson correlation analysis was performed to investigate correlation. Results Compared with the control group,the mixed hepatitis group,the cholestatic hepatitis group,and the simple cholestasis group had significant reductions in the expression of BSEP,MDR3,and MRP2 in liver tissue( F =48. 765,45. 424,and 77. 434,all P < 0. 05),and the comparison between any two groups showed that the cholestatic hepatitis group had significantly greater reductions than the mixed hepatitis group and the simple cholestasis group( all P < 0. 05). The degree of hepatocyte swelling and feather-like degeneration due to cholestasis increased with the reduction in the expression of BSEP,MRP2 and MDR3 in the area of cholestasis. In the cholestatic hepatitis group,BSEP was moderately negatively correlated with TBA( r =-0. 640,P = 0. 008),and in the simple cholestasis group,MRP2 was moderately negatively correlated with TBil( r =-0. 597,P = 0. 019) and DBil( r =-0. 643,P = 0. 011). Conclusion There are reductions in the positive expression of BSEP,MDR3,and MRP2 in each subtype of bile duct injury type of DILI,which is one of the important mechanisms of cholestasis in DILI.
- chemical and drug induced liver injury /
- carrier proteins /
- immunohistochemistry

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参考文献(15)

[1]CANTORE M,REINEHR R,SOMMERFELD A,et al.The Src family kinase Fyn mediates hyperosmolarity-induced Mrp2 and Bsep retrieval from canalicular membrane[J].J Biol Chem,2011,286(52):45014-45029．

[2]LEE JM,TRAUMER M,SOROKA CJ,et al.Expression of the bile aalt export is maintained after chronic cholestasis in the rat[J].Gastrocenterology,2000,118(1):163-172．

[3]Drug-induced Liver Disease Study Group,Chinese Society of Hepatology,Chinese Medical Association.Guidelines for the management of drug-induced liver injury[J].J Clin Hepatol,2015,31(11):1752-1769.(in Chinese)中华医学会肝病学分会药物性肝病学组．药物性肝损伤诊治指南[J]．临床肝胆病杂志，2015,31(11):1752-1769．

[4]STIEGER B.Role of the bile salt export pump,BSEP,in acquired forms of cholestasis[J].Drug Metab Rev,2010,42(3):437-445．

[5]RUSSMANN S,JETTER A,KULLAK-UBLICK GA.Pharmacogenetics of drug-induced liver injury[J].Hepatology,2010,52(2):748-761．

[6]DALY AK,DAY CP.Genetic association studies in drug-induced liver injury[J].Drug Metab Rev,2012,44(1):116-126．

[7]ARRESE M,ACCATINO L.From blood to bile:Recent advances in hepatobiliary transport[J].Ann Hepatol,2002,1(2):64-71．

[8]TUJIOS S,FONTANA RJ.Mechanisms of drug-induced liver injury:From bedside to bench[J].Nat Rev Gastroenterol Hepatol,2011,8(4):202-211．

[9] STIEGER B.Role of the bile salt export pump,BSEP,in acquired forms of cholestasis[J].Drug Metab Rev,2010,42(3):437-445．

[10]AKITA H,SUZUKI H,IO K,et al.Protection against post-ischemicm itochondrial injury in rat liver by silymarin or TUDC[J].Hepaol Res,2003,26:217-224．

[11]KEPPLER D,KNIG J.Hepatic secretion of conjugated drugs and endogenous substances[J].Semin Liver Dis,2000,20(3):265-272．

[12]TRAUNER M,BOYER JL.Bile salt transporters:Molecular characterization,function,and regulation[J].Physiol Rev,2003,83(2):633-671．

[13]TIETZ PS,MCNIVEN MA,SPLINTER PL,et al.Cytoskeletal and motor proteins facilitate trafficking of AQP1-containing vesicles in cholangiocytes[J].Biol Cell,2006,98(1):43-52．

[14]MARINELLI RA,LEHMANN GL,SORIA LR,et al.Hepatocyte aquaporins in bile formation and cholestasis[J].Front Biosci(Landmark Ed),2011,16(1):2642-2652．

[15]TRAUNER M,FICKERT P,HALIBASIC E,et al.Lessons from the toxicbile concept for the pathogenesis and treatment of cholestatic liver diseases[J].Wic Il Mcd Wochenschr,2008,158(19-20):542-548.

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