药物转运体在药源性肝损伤中的作用
|
摘要
肝脏是药物在体内代谢的最主要场所,药物在此进行一系列复杂的代谢转化,但是药物在预防和治疗疾病的同时,也可能造成肝损伤。细胞膜上存在很多功能性的蛋白,用于转运药物的蛋白被称为药物转运体,其在药物吸收、分布和消除的过程中发挥重要作用。近年,由于各种毒副作用而撤销市场的约四分之一的药品与药物转运体有关,因此,了解药物转运体的表达及功能对药源性肝损伤的发生机制具有重要意义。为促进临床合理用药,本文对药物转运体的分类、影响因素及在药源性肝损伤中的作用进行论述。
Drug metabolism in vivo majorly performed in liver, where a series of transformation of drug carry on. The drugs can prevent and treat diseases simultaneously, but they can also cause liver damage at the same time. As functional membrane proteins, drug transporters play a key role in the absorption, distribution and excretion of drug. Recently, a quarter of the drugs with side effects were associated with drug transporters have been revoked. Therefore, understanding the expression and function of the drug transporters is highly significant in terms of drug-induced liver damage mechanism. In order to promote rational drug application, this article summarized the classification, influence factors and the role of drug transporters in drug-induced liver injury.
Drug metabolism in vivo majorly performed in liver, where a series of transformation of drug carry on. The drugs can prevent and treat diseases simultaneously, but they can also cause liver damage at the same time. As functional membrane proteins, drug transporters play a key role in the absorption, distribution and excretion of drug. Recently, a quarter of the drugs with side effects were associated with drug transporters have been revoked. Therefore, understanding the expression and function of the drug transporters is highly significant in terms of drug-induced liver damage mechanism. In order to promote rational drug application, this article summarized the classification, influence factors and the role of drug transporters in drug-induced liver injury.
引文
[1]Larrey D.Epidemiology and individual susceptibility to adverse drug re-actions affecting the liver[J].Semin Liver Dis,2002,22(2):145-155
[2]Gobind A,Amir Z,Rohit L,et al.Targeting Dysbiosis for the Treatment of Liver Disease[J].Seminars in Liver Disease,2016,36(1):37-47
[3]Fromm M F,Kim RB.Drug Transporters[M].Erlangen:Springer Verlag Berlin Heidelberg,2011:5-11
[4]Houfu LP,Jasminder SP.Role of Hepatic Drug Transporters in Drug Development[J].Clin Pharmacol,2016,56(Suppl 7):S11-S22
[5]Donna AV.Transporter assays as useful in vitro tools in drug discovery and development[J].Expert Opinion on Drug Discovery,2016,11(1):91-103
[6]Clarke JD,Cherrington NJ.Genetics or environmentin drug transport:the case of organic anion transporting polypeptides and adverse drug reactions[J].Expert Opin Drug Metab Toxicol,2012,8(3):349-360
[7]Cressman AM,Petrovic V,Piquette-Miller M.Inflammation-mediated changes in drug transporter expression/activity:implications for therapeutic drug response[J].Expert Review of Clinical Pharmacology,2012,5(1):69-89
[8]Sissung TM,Troutman SM,Campbell TJ,et al.Transporter pharmacogenetics:ransporter polymorphismsaffect normal physiology,diseases,and pharmacotherapy[J].Discov Med,2012,13(68):19-34
[9]Katia S,Marc LV,Ziad AR,et al.Alteration of human hepatic drug transporter activity and expression by cigarette smoke condensate[J].Toxicology,2016,(363-364):58-71
[10]Tripathi A,Misra K,Kumar K,et al.Study of Some Piperine Analogues on Drugs Efflux by Targeting P-glycoprotein,an in silico Approach[J].Letters in Drug Design and Discovery,2016,13(9):952-961
[11]Borst P,Evers R,Kool M,et al.A family of drug transporters:the multidrug resistance-associated proteins[J].Natl Cancer Inst,2000,92:1295-1302
[12]Montanari F,Zdrazil B,Digles D,et al.Selectivity profiling of BCRP versus P-gp inhibition:from automated collection of polypharmacology data to multi-label learning[J].Journal of Cheminformatics,2016,8:1-13
[13]Carol JS,James LB.Biosynthesis and trafficking of the bile salt export pump,BSEP:Therapeutic implications of BSEP mutations[J].Molecular Aspects of Medicine,2014,37:3-14
[14]Amandla AB,Gavriel RB,Uma FM,et al.Effect of Disease Pathologies on Transporter Expression and Function[J].Clin Pharmacol,2016,56(Suppl 7):S205-S221
[15]许茜,许景峰.药物转运体介导的肿瘤细胞多药耐药研究进展[J/CD].中华临床医师杂志:电子版,2010,4:1643-1645Xu Qian,Xu Jing-feng.Research progress of drug transporter mediated multi-resistant in tumor cells[J].Chinese Journal of Clinicians,2010,4:1643-1645
[16]郭艺,蒋丽.大鼠体内有机阴离子多肽2表达的年龄特征[J].第四军医大学学报,2009,30(18):1700-1703Guo Yi,Jiang Li.Age characteriistics of Oatp2 in rat[J].Journal of the Fourth Military Medical University,2009,30(18):1700-1703
[17]Aleksunes LM,Yeager RL,Wen X,et al.Repression of hepatobiliary transporters and differential regulation of classic and alternative bile acid pathways in mice during pregnancy[J].Toxicol Sci,2012,130(2):257-268
[18]Jamie M,Bo K,Grace G,et al.Pharmacological Activation of Fxr Attenuates Pregnancy-Induced Repression of Hepatic and Ileal Bile Acid Transporters in Mice[J].The FASEB Journal,2015,29(1-Supplement):932-937
[19]Keppler D.Multidrug resistance proteins(MRPs,ABCCs):importance for pathophysiology and drug therapy[J].Handb Exp Pharmacol,2011,(201):299-323
[20]Tomita M,Takizawa Y,Kanbayashi A,et al.Suppression of efflux transporters in the intestines of endotoxin-treated rats[J].Int J Pharm,2012,428(1-2):33-38
[21]Andreas G,Gernot Z,Christoph GD,et al.Cytokine-independent repression of rodent ntcp in obstructive cholestasis[J].Hepatology,2005,41(3):470-477
[22]Petrovic V,Teng S,Piquette-Miller M.Regulation of drug transporters during infection and inflammation[J].Mol Interv,2007,7(2):99-111
[23]Lea S,Jean P,Christian D,et al.Implication of hepatic transporters(MDR1 and MRP2)in inflammation-associated idiosyncratic drug-induced epatotoxicity investigated by microvolume cytometry[J].Cytometry Part A,2013,83(4):403-408
[24]Aoki K,Nakajima M,Hoshi Y,et al.Effect of aminoguanidine on lipopolysaccharide-induced changes in rat liver transporters and transcription factors[J].Biol Pharm Bull,2008,31(3):412-420
[25]Alice CR,Rui C,Fabiana DV,et al.The expression of efflux and uptake transporters are regulated by statins in Caco-2 and Hep G2 cells[J].Acta Pharmacol Sin,2009,30(7):956-964
[26]Syed SB,Coumar MS1.P-Glycoprotein Mediated Multidrug Resistance Reversal by Phytochemicals:A Review of SAR&Future Perspective for Drug Design[J].Curr Top Med Chem,2016,16(22):2484-2508
[27]Kim JH,Chae M,Choi AR,et al.SP600125 overcomes antimitotic drug-resistance in cancer cells by increasing apoptosis with independence of P-gp inhibition[J].Eur J Pharmacol,2014,723:141-147
[28]Lasse S,Hans C,Cederberg H,et al.IPEC-J2 MDR1,a Novel High-Resistance Cell Line with Functional Expression of Human P glycoprotein(ABCB1)for Drug Screening Studies[J].Molecu lar Pharmaceutics,2016,13(2):640-652
[29]Annaert PP,Turncliff RZ,Booth CL,et al.P-glycoprotein mediated in vitro biliary excretion in sandwich-cultured rat hepatocytes[J].Drug Metab Dispos,2001,29(10):1277-1283
[30]金实,姚丹,刘灿,等.慢性肝损伤对大鼠脑内P-GP及MRP2功能和表达的影响[J].中国药科大学学报,2012,43(1):64-69Jin Shi,Yao Dan,Liu Can,et al.Effect of chronic liver failure on the function and expression of P-GP and MRP2 in rat brain[J].Journal of China Pharmaceutical University,2012,43(1):64-69
[31]Arana MR,Tocchetti GN,Rigalli JP,et al.Physiological and pathophysiological factors affecting the expression and activity of the drug transporter MRP2 in intestine:Impact on its function as membrane barrier[J].Pharmacol Res,2016,109:32-44
[32]Sun Peng-yuan,Wang Chang-yuan,Liu Qi,et al.OATP and MRP2-mediated hepatic uptake and biliary excretion of eprosartan in rat and human[J].Pharmacological Reports,2014,66(2):311-319
[33]Zhang Ai-jie,Jia Yong-ming,Xu Qing-han,et al.Dioscin protects against ANIT-induced cholestasis via regulating Oatps,Mrp2 and Bsep expression in rats[J].Toxicol Appl Pharmacol,2016,305:127-135
[34]朱蓉,马越鸣.肝细胞药物转运体研究进展[J].中国药理学与毒理学杂志,2014,28(5):806-810Zhu Rong,Ma Yue-ming.Research progress on the hepatocyte drug transpoter[J].Chinese Journal of Pharmacology and Toxicology,2014,28(5):806-810
[35]Bomzon A,Ljubuncic P,Said O,et al.Ursodeoxycholic acid and in vitro vasoactivity of hydrophobic bile acids[J].Dig Dis Sci,2001,46(9):2017-2024
[36]Zweers,SJ,Booij,KA,Komuta M,et al.The human gallbladder secretes fibroblast growth factor 19 into bile:towards defining the role of fibroblast growth factor 19 in the enterobiliary tract[J].Hepatology,2012,55(22):575-583
[37]Hisaeda K,Inokuchi A,Nakamura T,et al.Interleukin-1beta represses MRP2 gene expression through inactivation of interferon regulatory factor 3 in Hep G2 cells[J].Hepatology,2004,39(6):1574-1582
[38]Alrefai WA,Gill RK.Bile acid transporters:structure,function,regulation and pathophysiological implications[J].Pharm Res,2007,24(10):1803-1823
[39]Dietrich K.The Roles of MRP2,MRP3,OATP1B1,and OATP1B3in Conjugated Hyperbilirubinemia[J].Drug Metab Dispos,2014,42(4):561-565
[40]胡文杰,黎东明,陈伟,等.多药耐药相关蛋2、3与原发性肝癌合并门静脉癌栓术后辅助化疗疗效的相关性研究[J].中华普通外杂志,2014,8(5):376-380Hu Wen-jie,Li Dong-ming,Chen Wei,et al.Study on the correlation between the expression of MRP2 and MRP3 and efficacy of chemotherapy in hepatocellular carcinoma patients with tumor thrombi in major portal vein[J].Chinese Archives of General Surgery,2014,8(5):376-380
[41]Zhou Li-ting,Song Yan-qing,Zhao Jing,et al.Monoammonium glycyrrhizinate protects rifampicin-and isoniazid-induced hepatotoxicity via regulating the expression of ransporter Mrp2,Ntcp,and Oatp1a4 in liver[J].Pharmaceutical Biology,2016,54(6):931-937
[42]Morgan RE,Chen Y,Kalyanaraman N,et al.A multifactorial approach to hepatobiliary transporter assessment enables improved therapeutic compound development[J].Toxicol.Sci,2013,136(1):216-241
[43]Tomoko W,Manami M,Toshinobu,et al.Utility of Bilirubins and Bile Acids as Endogenous Biomarkers for the Inhibition of Hepatic Transporters[J].Drug Metab Dispos,2015,43(4):459-466
[44]ágnes T,LászlóH.Recent advances in the exploration of the bile salt export pump(BSEP/ABCB11)function[J].Expert Opinion on Therapeutic Targets,2016,20(4):501-514
[45]孔凡民,隋春阳,李航宇,等.胆囊结石形成与胆盐转运子BSEP、MRP2、NTCP关系的研究[J].中华肝胆外科杂志,2006,12(3):161-163Kong Fan-min,Sui Chun-yang,Li Hang-yu,et al.Relation of bile salt transporter BSEP,MRP2 and NTCP to cholelithiasis[J].Chinese Journal of Hepatobiliary Surgery,2006,12(3):161-163
[46]周利婷,周燕,张国强,等.异烟肼对小鼠肝细胞膜转运体Mrp2,Bsep,P-gp和Ntcp表达的影响[J].中国药学杂志,2014,49(4):298-302Zhou Li-ting,Zhou Yan,Zhang Guo-qiang,et al.Effect of Isoniazid on the Expression of Hepatobiliary Membrane Transporters Mrp2,Bsep,Pgp and Ntcp in Mouse[J].Chinese Pharmaceutical Journal,2014,49(4):298-302
[47]Jae HC,Emile P,Jonathan C,et al.Evaluating the In Vitro Inhibition of UGT1A1,OATP1B1,OATP1B3,MRP2,and BSEP in Predicting Drug-Induced Hyperbilirubinemia[J].Mol.Pharmaceutics,2013,10(8):Mol.Pharmaceutics,2013,10(8):3067-3075
[48]Venkata V M,Saskia F,Annett K,et al.Interaction of human organic anion transporter 2(OAT2)and sodium taurocholate cotransporting polypeptide(NTCP)with antineoplastic drugs[J].Pharmacological Research,2015,91:78-87
[49]Shin HJ,Lee CH,Lee SS,et al.Identification of genetic polymorphisms of human OAT1 and OAT2 genes and their relationship to OAT2 expression in human liver[J].Clin Chim Acta,2010,411(1-2):99-105
[50]Popowski K,Eloranta JJ,Saborowski M,et al.The human organic anion transporter 2 gene is transactivated by hepatocyte nuclear factor-4 alpha and suppressed by bileacids[J].Mol Pharmacol,2005,67(5):1629-1638
[51]Chen Hao,Huang Xiao-tao,Min Jian-bin,et al.Geniposidic acid protected against ANIT-induced hepatotoxity and acute intrahepatic cholestasis,due to Fxr-mediated regulation of Bsepand Mrp2[J].Journal of Ethnopharmacology,2016,179:197-207
[52]Liu Yan,Pu Qiang-hong,Wu Ming-jun,et al.Proteomic analysis for the impact of hypercholesterolemia on expressions of hepatic drug transporters and metabolizing enzymes[J].Xenobiotica,2016,46(10):940-947
[53]Aoki K,Saso N,Kato S,et al.Nitric oxide and peroxynitrite regulate transporter transcription in rat liver slices[J].Biol Pharm Bull,2008,31(10):1882-1887
[54]Cha SH,Kim HP,Jung NH,et al.Down-regulation of organic anion transporter 2 m RNA expression by nitric oxide in primary cultured rat hepatocytes[J].IUBMB Life,2002,54(3):129-135
[55]Theile D,Haefeli WE,Seitz HK,et al.Association of liver stiffness with hepatic expression of pharmacokinetically important genes in alcoholic liver disease[J].Alcohol Clin Exp Res,2013,37(Suppl 1):E17-E22
[56]Yin J,Wang J.Renal drug transporters and their significance in drug drug interactions[J].Acta Pharmaceutica Sinica B,2016,6(5):363-373
[57]Nies AT,Koepsell H,Winter S,et al.Expression of organic cation transporters OCT1(SLC22A1)and OCT3(SLC22A3)isaffected by genetic factors and cholestasis in human liver[J].Hepatology,2009,50(4):1227-1240
[58]Heise M,Lautem A,Knapstein J,et al.Downregulation of organic cation transporters OCT1(SLC22A1)and OCT3(SLC22A3)in human hepatocellular carcinoma and their prognostic significance[J].BMC Cancer,2012,12:109-119
[59]Zhang Guo-qiang,Zhou Yan,Rao Zhi,et al.Effect of Yin-Zhi-Huang on up-regulation of Oatp2,Ntcp,and Mrp2 proteins in estrogeninduced rat cholestasis[J].Pharmaceutical Biology,2015,53(3):319-325
[60]Guo Yao-xue,Xu Xue-fei,Zhang Qi-zhi,et al.The inhibition of hepatic bile acids transporters Ntcp and Bsep is involved in the pathogenesis of isoniazid/rifampicin-induced hepatotoxicity[J].Toxicology Mechanisms and Methods,2015,25(5):382-387
[61]Geier A,Kim S,Gerloff T,et al.Hepatobiliary organic anion transporters are differentially regulated in acute toxic liver injury induced by carbon tetrachloride[J].Journal of Hepatology,2002,37(2):198-205
[62]Yan Huan,Liu Yang,Sui Jian-hua,et al.NTCP opens the door for hepatitis B virus infection[J].Antiviral Research,2015,121:24-30
[63]Wenhui L,Stephan U.Entry of hepatitis B and hepatitis D virus into hepatocytes:Basic insights and clinical implications[J].Hepatol,2016,64(1Suppl):S32-S40
[2]Gobind A,Amir Z,Rohit L,et al.Targeting Dysbiosis for the Treatment of Liver Disease[J].Seminars in Liver Disease,2016,36(1):37-47
[3]Fromm M F,Kim RB.Drug Transporters[M].Erlangen:Springer Verlag Berlin Heidelberg,2011:5-11
[4]Houfu LP,Jasminder SP.Role of Hepatic Drug Transporters in Drug Development[J].Clin Pharmacol,2016,56(Suppl 7):S11-S22
[5]Donna AV.Transporter assays as useful in vitro tools in drug discovery and development[J].Expert Opinion on Drug Discovery,2016,11(1):91-103
[6]Clarke JD,Cherrington NJ.Genetics or environmentin drug transport:the case of organic anion transporting polypeptides and adverse drug reactions[J].Expert Opin Drug Metab Toxicol,2012,8(3):349-360
[7]Cressman AM,Petrovic V,Piquette-Miller M.Inflammation-mediated changes in drug transporter expression/activity:implications for therapeutic drug response[J].Expert Review of Clinical Pharmacology,2012,5(1):69-89
[8]Sissung TM,Troutman SM,Campbell TJ,et al.Transporter pharmacogenetics:ransporter polymorphismsaffect normal physiology,diseases,and pharmacotherapy[J].Discov Med,2012,13(68):19-34
[9]Katia S,Marc LV,Ziad AR,et al.Alteration of human hepatic drug transporter activity and expression by cigarette smoke condensate[J].Toxicology,2016,(363-364):58-71
[10]Tripathi A,Misra K,Kumar K,et al.Study of Some Piperine Analogues on Drugs Efflux by Targeting P-glycoprotein,an in silico Approach[J].Letters in Drug Design and Discovery,2016,13(9):952-961
[11]Borst P,Evers R,Kool M,et al.A family of drug transporters:the multidrug resistance-associated proteins[J].Natl Cancer Inst,2000,92:1295-1302
[12]Montanari F,Zdrazil B,Digles D,et al.Selectivity profiling of BCRP versus P-gp inhibition:from automated collection of polypharmacology data to multi-label learning[J].Journal of Cheminformatics,2016,8:1-13
[13]Carol JS,James LB.Biosynthesis and trafficking of the bile salt export pump,BSEP:Therapeutic implications of BSEP mutations[J].Molecular Aspects of Medicine,2014,37:3-14
[14]Amandla AB,Gavriel RB,Uma FM,et al.Effect of Disease Pathologies on Transporter Expression and Function[J].Clin Pharmacol,2016,56(Suppl 7):S205-S221
[15]许茜,许景峰.药物转运体介导的肿瘤细胞多药耐药研究进展[J/CD].中华临床医师杂志:电子版,2010,4:1643-1645Xu Qian,Xu Jing-feng.Research progress of drug transporter mediated multi-resistant in tumor cells[J].Chinese Journal of Clinicians,2010,4:1643-1645
[16]郭艺,蒋丽.大鼠体内有机阴离子多肽2表达的年龄特征[J].第四军医大学学报,2009,30(18):1700-1703Guo Yi,Jiang Li.Age characteriistics of Oatp2 in rat[J].Journal of the Fourth Military Medical University,2009,30(18):1700-1703
[17]Aleksunes LM,Yeager RL,Wen X,et al.Repression of hepatobiliary transporters and differential regulation of classic and alternative bile acid pathways in mice during pregnancy[J].Toxicol Sci,2012,130(2):257-268
[18]Jamie M,Bo K,Grace G,et al.Pharmacological Activation of Fxr Attenuates Pregnancy-Induced Repression of Hepatic and Ileal Bile Acid Transporters in Mice[J].The FASEB Journal,2015,29(1-Supplement):932-937
[19]Keppler D.Multidrug resistance proteins(MRPs,ABCCs):importance for pathophysiology and drug therapy[J].Handb Exp Pharmacol,2011,(201):299-323
[20]Tomita M,Takizawa Y,Kanbayashi A,et al.Suppression of efflux transporters in the intestines of endotoxin-treated rats[J].Int J Pharm,2012,428(1-2):33-38
[21]Andreas G,Gernot Z,Christoph GD,et al.Cytokine-independent repression of rodent ntcp in obstructive cholestasis[J].Hepatology,2005,41(3):470-477
[22]Petrovic V,Teng S,Piquette-Miller M.Regulation of drug transporters during infection and inflammation[J].Mol Interv,2007,7(2):99-111
[23]Lea S,Jean P,Christian D,et al.Implication of hepatic transporters(MDR1 and MRP2)in inflammation-associated idiosyncratic drug-induced epatotoxicity investigated by microvolume cytometry[J].Cytometry Part A,2013,83(4):403-408
[24]Aoki K,Nakajima M,Hoshi Y,et al.Effect of aminoguanidine on lipopolysaccharide-induced changes in rat liver transporters and transcription factors[J].Biol Pharm Bull,2008,31(3):412-420
[25]Alice CR,Rui C,Fabiana DV,et al.The expression of efflux and uptake transporters are regulated by statins in Caco-2 and Hep G2 cells[J].Acta Pharmacol Sin,2009,30(7):956-964
[26]Syed SB,Coumar MS1.P-Glycoprotein Mediated Multidrug Resistance Reversal by Phytochemicals:A Review of SAR&Future Perspective for Drug Design[J].Curr Top Med Chem,2016,16(22):2484-2508
[27]Kim JH,Chae M,Choi AR,et al.SP600125 overcomes antimitotic drug-resistance in cancer cells by increasing apoptosis with independence of P-gp inhibition[J].Eur J Pharmacol,2014,723:141-147
[28]Lasse S,Hans C,Cederberg H,et al.IPEC-J2 MDR1,a Novel High-Resistance Cell Line with Functional Expression of Human P glycoprotein(ABCB1)for Drug Screening Studies[J].Molecu lar Pharmaceutics,2016,13(2):640-652
[29]Annaert PP,Turncliff RZ,Booth CL,et al.P-glycoprotein mediated in vitro biliary excretion in sandwich-cultured rat hepatocytes[J].Drug Metab Dispos,2001,29(10):1277-1283
[30]金实,姚丹,刘灿,等.慢性肝损伤对大鼠脑内P-GP及MRP2功能和表达的影响[J].中国药科大学学报,2012,43(1):64-69Jin Shi,Yao Dan,Liu Can,et al.Effect of chronic liver failure on the function and expression of P-GP and MRP2 in rat brain[J].Journal of China Pharmaceutical University,2012,43(1):64-69
[31]Arana MR,Tocchetti GN,Rigalli JP,et al.Physiological and pathophysiological factors affecting the expression and activity of the drug transporter MRP2 in intestine:Impact on its function as membrane barrier[J].Pharmacol Res,2016,109:32-44
[32]Sun Peng-yuan,Wang Chang-yuan,Liu Qi,et al.OATP and MRP2-mediated hepatic uptake and biliary excretion of eprosartan in rat and human[J].Pharmacological Reports,2014,66(2):311-319
[33]Zhang Ai-jie,Jia Yong-ming,Xu Qing-han,et al.Dioscin protects against ANIT-induced cholestasis via regulating Oatps,Mrp2 and Bsep expression in rats[J].Toxicol Appl Pharmacol,2016,305:127-135
[34]朱蓉,马越鸣.肝细胞药物转运体研究进展[J].中国药理学与毒理学杂志,2014,28(5):806-810Zhu Rong,Ma Yue-ming.Research progress on the hepatocyte drug transpoter[J].Chinese Journal of Pharmacology and Toxicology,2014,28(5):806-810
[35]Bomzon A,Ljubuncic P,Said O,et al.Ursodeoxycholic acid and in vitro vasoactivity of hydrophobic bile acids[J].Dig Dis Sci,2001,46(9):2017-2024
[36]Zweers,SJ,Booij,KA,Komuta M,et al.The human gallbladder secretes fibroblast growth factor 19 into bile:towards defining the role of fibroblast growth factor 19 in the enterobiliary tract[J].Hepatology,2012,55(22):575-583
[37]Hisaeda K,Inokuchi A,Nakamura T,et al.Interleukin-1beta represses MRP2 gene expression through inactivation of interferon regulatory factor 3 in Hep G2 cells[J].Hepatology,2004,39(6):1574-1582
[38]Alrefai WA,Gill RK.Bile acid transporters:structure,function,regulation and pathophysiological implications[J].Pharm Res,2007,24(10):1803-1823
[39]Dietrich K.The Roles of MRP2,MRP3,OATP1B1,and OATP1B3in Conjugated Hyperbilirubinemia[J].Drug Metab Dispos,2014,42(4):561-565
[40]胡文杰,黎东明,陈伟,等.多药耐药相关蛋2、3与原发性肝癌合并门静脉癌栓术后辅助化疗疗效的相关性研究[J].中华普通外杂志,2014,8(5):376-380Hu Wen-jie,Li Dong-ming,Chen Wei,et al.Study on the correlation between the expression of MRP2 and MRP3 and efficacy of chemotherapy in hepatocellular carcinoma patients with tumor thrombi in major portal vein[J].Chinese Archives of General Surgery,2014,8(5):376-380
[41]Zhou Li-ting,Song Yan-qing,Zhao Jing,et al.Monoammonium glycyrrhizinate protects rifampicin-and isoniazid-induced hepatotoxicity via regulating the expression of ransporter Mrp2,Ntcp,and Oatp1a4 in liver[J].Pharmaceutical Biology,2016,54(6):931-937
[42]Morgan RE,Chen Y,Kalyanaraman N,et al.A multifactorial approach to hepatobiliary transporter assessment enables improved therapeutic compound development[J].Toxicol.Sci,2013,136(1):216-241
[43]Tomoko W,Manami M,Toshinobu,et al.Utility of Bilirubins and Bile Acids as Endogenous Biomarkers for the Inhibition of Hepatic Transporters[J].Drug Metab Dispos,2015,43(4):459-466
[44]ágnes T,LászlóH.Recent advances in the exploration of the bile salt export pump(BSEP/ABCB11)function[J].Expert Opinion on Therapeutic Targets,2016,20(4):501-514
[45]孔凡民,隋春阳,李航宇,等.胆囊结石形成与胆盐转运子BSEP、MRP2、NTCP关系的研究[J].中华肝胆外科杂志,2006,12(3):161-163Kong Fan-min,Sui Chun-yang,Li Hang-yu,et al.Relation of bile salt transporter BSEP,MRP2 and NTCP to cholelithiasis[J].Chinese Journal of Hepatobiliary Surgery,2006,12(3):161-163
[46]周利婷,周燕,张国强,等.异烟肼对小鼠肝细胞膜转运体Mrp2,Bsep,P-gp和Ntcp表达的影响[J].中国药学杂志,2014,49(4):298-302Zhou Li-ting,Zhou Yan,Zhang Guo-qiang,et al.Effect of Isoniazid on the Expression of Hepatobiliary Membrane Transporters Mrp2,Bsep,Pgp and Ntcp in Mouse[J].Chinese Pharmaceutical Journal,2014,49(4):298-302
[47]Jae HC,Emile P,Jonathan C,et al.Evaluating the In Vitro Inhibition of UGT1A1,OATP1B1,OATP1B3,MRP2,and BSEP in Predicting Drug-Induced Hyperbilirubinemia[J].Mol.Pharmaceutics,2013,10(8):Mol.Pharmaceutics,2013,10(8):3067-3075
[48]Venkata V M,Saskia F,Annett K,et al.Interaction of human organic anion transporter 2(OAT2)and sodium taurocholate cotransporting polypeptide(NTCP)with antineoplastic drugs[J].Pharmacological Research,2015,91:78-87
[49]Shin HJ,Lee CH,Lee SS,et al.Identification of genetic polymorphisms of human OAT1 and OAT2 genes and their relationship to OAT2 expression in human liver[J].Clin Chim Acta,2010,411(1-2):99-105
[50]Popowski K,Eloranta JJ,Saborowski M,et al.The human organic anion transporter 2 gene is transactivated by hepatocyte nuclear factor-4 alpha and suppressed by bileacids[J].Mol Pharmacol,2005,67(5):1629-1638
[51]Chen Hao,Huang Xiao-tao,Min Jian-bin,et al.Geniposidic acid protected against ANIT-induced hepatotoxity and acute intrahepatic cholestasis,due to Fxr-mediated regulation of Bsepand Mrp2[J].Journal of Ethnopharmacology,2016,179:197-207
[52]Liu Yan,Pu Qiang-hong,Wu Ming-jun,et al.Proteomic analysis for the impact of hypercholesterolemia on expressions of hepatic drug transporters and metabolizing enzymes[J].Xenobiotica,2016,46(10):940-947
[53]Aoki K,Saso N,Kato S,et al.Nitric oxide and peroxynitrite regulate transporter transcription in rat liver slices[J].Biol Pharm Bull,2008,31(10):1882-1887
[54]Cha SH,Kim HP,Jung NH,et al.Down-regulation of organic anion transporter 2 m RNA expression by nitric oxide in primary cultured rat hepatocytes[J].IUBMB Life,2002,54(3):129-135
[55]Theile D,Haefeli WE,Seitz HK,et al.Association of liver stiffness with hepatic expression of pharmacokinetically important genes in alcoholic liver disease[J].Alcohol Clin Exp Res,2013,37(Suppl 1):E17-E22
[56]Yin J,Wang J.Renal drug transporters and their significance in drug drug interactions[J].Acta Pharmaceutica Sinica B,2016,6(5):363-373
[57]Nies AT,Koepsell H,Winter S,et al.Expression of organic cation transporters OCT1(SLC22A1)and OCT3(SLC22A3)isaffected by genetic factors and cholestasis in human liver[J].Hepatology,2009,50(4):1227-1240
[58]Heise M,Lautem A,Knapstein J,et al.Downregulation of organic cation transporters OCT1(SLC22A1)and OCT3(SLC22A3)in human hepatocellular carcinoma and their prognostic significance[J].BMC Cancer,2012,12:109-119
[59]Zhang Guo-qiang,Zhou Yan,Rao Zhi,et al.Effect of Yin-Zhi-Huang on up-regulation of Oatp2,Ntcp,and Mrp2 proteins in estrogeninduced rat cholestasis[J].Pharmaceutical Biology,2015,53(3):319-325
[60]Guo Yao-xue,Xu Xue-fei,Zhang Qi-zhi,et al.The inhibition of hepatic bile acids transporters Ntcp and Bsep is involved in the pathogenesis of isoniazid/rifampicin-induced hepatotoxicity[J].Toxicology Mechanisms and Methods,2015,25(5):382-387
[61]Geier A,Kim S,Gerloff T,et al.Hepatobiliary organic anion transporters are differentially regulated in acute toxic liver injury induced by carbon tetrachloride[J].Journal of Hepatology,2002,37(2):198-205
[62]Yan Huan,Liu Yang,Sui Jian-hua,et al.NTCP opens the door for hepatitis B virus infection[J].Antiviral Research,2015,121:24-30
[63]Wenhui L,Stephan U.Entry of hepatitis B and hepatitis D virus into hepatocytes:Basic insights and clinical implications[J].Hepatol,2016,64(1Suppl):S32-S40