雷公藤甲素致小鼠肝损伤对转运体Mrp2和Oatp2的影响
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- 英文论文题名：The Effects of Triptolide Induced Liver Injury on Hepatobiliary Membrane Transporter Mrp2 and Oatp2
- 论文作者：周利婷 ; 曲晓宇 ; 陶娌娜 ; 牛俊奇 ; 丁艳华 ; 宋燕青
- 英文论文作者：ZHOU Li-ting ; QU Xiao-yu ; TAO Li-na ; NIU Jun-qi ; DING Yan-hua ; SONG Yan-qing ; Dept.Pharmacy ; The First Hospital of Jilin University ; Dept.Hepatology ; The First Hospital of Jilin University ; Dept.Ward of Phase Ⅰ Clinical Drug Trials ; The First Hospital of Jilin University
- 年：2016
- 作者机构：吉林大学第一医院药学部;吉林大学第一医院肝胆胰内科;吉林大学第一医院Ⅰ期药物临床试验病房;
- 论文关键词：雷公藤甲素 ; 肝细胞膜转运体 ; 多药耐药相关蛋白2 ; 有机阴离子转运多肽2
- 英文论文关键词：triptolide ; hepatobiliary membrane transporter ; multidrug resistance protein 2 ; organic anion transporting polypeptides 2
- 会议召开时间：2016-09-27
- 会议录名称：中国药学会第十三届青年药学科研成果交流会论文集
- 语种：中文
- 分类号：R285.5
- 学会代码：YYWS
- 会议名称：中国药学会第十三届青年药学科研成果交流会
- 会议地点：中国江西南昌
- 主办单位：中国药学会
- 学会名称：中国药学会
- 页数：5
- 文件大小：728k
- 原文格式：O
- 会议级别：全国
摘要
目的:本文基于多药耐药相关蛋白2(multidrug resistance protein 2,Mrp2)和有机阴离子转运多肽2(organic anion transporting polypeptides 2,Oatp2)初步探究雷公藤甲素诱导小鼠肝损伤的机制。方法:ICR小鼠单次灌胃给予雷公藤甲素(1.0 mg·kg~(-1))24 h后称重,摘眼球采血后分离血清,测定血清生化指标;取肝组织做病理切片;采用免疫印迹法检测肝脏组织中Mrp2和Oatp2的蛋白表达量。结果:与对照组相比,雷公藤甲素组肝重指数显著增加(P<0.05),部分血清生化指标显著上升(P<0.05),且肝细胞发生核碎裂和脂肪变性。雷公藤甲素组Oatp2的表达较对照组显著升高了32.79%(P<0.05),而Mrp2的表达较对照组显著下降了45.47%(P<0.01)。结论:雷公藤甲素可能通过上调肝细胞膜转运体Oatp2和下调Mrp2,扰乱肝内胆红素和胆汁酸代谢排泄平衡,可能是雷公藤甲素诱导肝损伤的机制之一。
OBJECTIVE Triptolide(TP) is a promising agent for the treatment of numbers of autoimmune diseases.However,high incidence of liver toxicity is believed to be the main cause of discontinued the treatment.The aim of this study was to investigate the mechanisms of tritolide induced liver injury in mice which was based on the hepatobiliary membrane transporters of multidrug resistance protein 2(Mrp2) and organic anion transporting polypeptides 2(Oatp2).METHODS Male ICR mice were randomly divided into two groups:control and triptolide group(n=8).Mice in triptolide group were orally administered with triptolide(1.0 mg·kg~(-1)) once,while mice in control group were orally administered with 0.5%CMC-Na.The eyeballs were excracted for blood and separate the serum at24 h after administered.The serum was obtained for biochemical analysis.Livers were harvested immediately,a portion of liver was for histological analysis;the rests were frozen and stored for western blot analysis.RESULTS Compared to the control group,the liver indexes were significantly elevated after triptolide administration.The triptolide treatment significantly increased the AST,ALT,ALP,TBIL and IBIL levels compared to control group(P<0.05).The pathological of livers in triptolide group shows karyorrhexis and fatty degeneration.Compared to control group,the expression of Oatp2 were obviously increased to 32.79%(P<0.05) and Mrp2 were significantly reduced to 45.47%(P<0.01) in triptolide group.CONCLUSION The underlying mechanism of triptolide induced liver injury is related to the up-regulation of Oatp2 and the down-regulation of Mrp2.
OBJECTIVE Triptolide(TP) is a promising agent for the treatment of numbers of autoimmune diseases.However,high incidence of liver toxicity is believed to be the main cause of discontinued the treatment.The aim of this study was to investigate the mechanisms of tritolide induced liver injury in mice which was based on the hepatobiliary membrane transporters of multidrug resistance protein 2(Mrp2) and organic anion transporting polypeptides 2(Oatp2).METHODS Male ICR mice were randomly divided into two groups:control and triptolide group(n=8).Mice in triptolide group were orally administered with triptolide(1.0 mg·kg~(-1)) once,while mice in control group were orally administered with 0.5%CMC-Na.The eyeballs were excracted for blood and separate the serum at24 h after administered.The serum was obtained for biochemical analysis.Livers were harvested immediately,a portion of liver was for histological analysis;the rests were frozen and stored for western blot analysis.RESULTS Compared to the control group,the liver indexes were significantly elevated after triptolide administration.The triptolide treatment significantly increased the AST,ALT,ALP,TBIL and IBIL levels compared to control group(P<0.05).The pathological of livers in triptolide group shows karyorrhexis and fatty degeneration.Compared to control group,the expression of Oatp2 were obviously increased to 32.79%(P<0.05) and Mrp2 were significantly reduced to 45.47%(P<0.01) in triptolide group.CONCLUSION The underlying mechanism of triptolide induced liver injury is related to the up-regulation of Oatp2 and the down-regulation of Mrp2.
引文
[1]吴霞,王忠震,林兵,等.雷公藤毒性作用机制研究进展[J].中国医院药学杂志,2015,8(35):1519-1523.
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[3]Ling-Lei Kong,Xiao-Mei Zhuang,Hai-Ying Yang,et al.Inhibition of P-glycoprotein Gene Expression and Function Enhances Triptolideinduced Hepatotoxicity in Mice[J].Sci Rep,2015,5:11747.
[4]赵庆华,孙蓉.雷公藤片对迟发型超敏反应小鼠的药效与肝脏伴随毒副作用研究[J].中国实验方剂学,2016,22(3):156-159.
[5]张鑫.雷公藤制剂毒副作用及减毒方法研究进展[J].中国药学杂志,2013,48(11):1897-1901.
[6]王丹,饶志,武新安.药物转运体所介导的药物相互作用[J].中国医院药学杂志,2013,33(5):397-399.
[7]Dietrich CG,Geier A.Effect of drug transporter pharmacogenetics on cholestasis[J].Expert Opin Drug Metab Toxicol,2014,10(11):1533-51.
[8]Zolk O and Fromm MF.Transporter-mediated drug uptake and efflux:important determinants of adverse drug reactions[J].Clin Pharmacol Ther,2011,89:798-805.
[9]周利婷,宋燕青,曲晓宇,等.甘草酸单铵保护利福平致大鼠肝损伤的机制初探[J].中国医院药学杂志,2015,35(18):1650-1654.
[10]Corsini A and M Bortolini.Drug-induced liver injury:the role of drug metabolism and transport[J].J Clin Pharmacol,2013,53:463-474.
[11]Reichel C,B Gao,et al.Localization and function of the organic anion-transporting polypeptide Oatp2 in rat liver[J].Gastroenterology,1999,117:688-695.
[12]Keppler D.The roles of MRP2,MRP3,OATP1B1,and OATP1B3 in conjugated hyperbilirubinemia^.Drug Metab Dispos,2014,42(4):561-5.
[13]Doring B,Petzinger E.Phase 0 and phase III transport in various organs:combined concept of phases in xenobiotic transport and metabolism[J].Drug Metab Rev,2014,46(3):261-82.
[14]Leslie EM.Arsenic-glutathione conjugate transport by the human multidrug resistance proteins(MRPs/ABCCs)[J].J Inorg Biochem,2012,108:141-9.
[15]Devarbhavi H.An Update on Drug-induced Liver Injury[J].J Clin Exp Hepatol,2012,2(3):247-59.
[2]魏婕,顾一煌,李广林,等.雷公藤甲素肝毒性作用机制研究进展[J].山东中医杂志,2012,3l(9):693-695.
[3]Ling-Lei Kong,Xiao-Mei Zhuang,Hai-Ying Yang,et al.Inhibition of P-glycoprotein Gene Expression and Function Enhances Triptolideinduced Hepatotoxicity in Mice[J].Sci Rep,2015,5:11747.
[4]赵庆华,孙蓉.雷公藤片对迟发型超敏反应小鼠的药效与肝脏伴随毒副作用研究[J].中国实验方剂学,2016,22(3):156-159.
[5]张鑫.雷公藤制剂毒副作用及减毒方法研究进展[J].中国药学杂志,2013,48(11):1897-1901.
[6]王丹,饶志,武新安.药物转运体所介导的药物相互作用[J].中国医院药学杂志,2013,33(5):397-399.
[7]Dietrich CG,Geier A.Effect of drug transporter pharmacogenetics on cholestasis[J].Expert Opin Drug Metab Toxicol,2014,10(11):1533-51.
[8]Zolk O and Fromm MF.Transporter-mediated drug uptake and efflux:important determinants of adverse drug reactions[J].Clin Pharmacol Ther,2011,89:798-805.
[9]周利婷,宋燕青,曲晓宇,等.甘草酸单铵保护利福平致大鼠肝损伤的机制初探[J].中国医院药学杂志,2015,35(18):1650-1654.
[10]Corsini A and M Bortolini.Drug-induced liver injury:the role of drug metabolism and transport[J].J Clin Pharmacol,2013,53:463-474.
[11]Reichel C,B Gao,et al.Localization and function of the organic anion-transporting polypeptide Oatp2 in rat liver[J].Gastroenterology,1999,117:688-695.
[12]Keppler D.The roles of MRP2,MRP3,OATP1B1,and OATP1B3 in conjugated hyperbilirubinemia^.Drug Metab Dispos,2014,42(4):561-5.
[13]Doring B,Petzinger E.Phase 0 and phase III transport in various organs:combined concept of phases in xenobiotic transport and metabolism[J].Drug Metab Rev,2014,46(3):261-82.
[14]Leslie EM.Arsenic-glutathione conjugate transport by the human multidrug resistance proteins(MRPs/ABCCs)[J].J Inorg Biochem,2012,108:141-9.
[15]Devarbhavi H.An Update on Drug-induced Liver Injury[J].J Clin Exp Hepatol,2012,2(3):247-59.