基于特异质大鼠胆红素相关转运体功能抑制探讨首乌藤肝损伤机制(1)
[摘要]考察全粉及提取物对正常和特异质(LPS)大鼠胆红素相关转运体Oatp1a1，Oatp1b2和MRP2活性及mRNA表达的影响，探讨首乌藤致肝损伤的可能机制。正常及LPS大鼠分别连续灌胃首乌藤全粉及提取物7 d后，静脉注射转运体底物磺溴酞钠(BSP)，测定其药动学参数，考察各转运体的活性，同时取肝组织检测转运体mRNA的表达。结果首乌藤全粉及提取物可使BSP的t1/2和AUC显著升高，CL显著降低；AST和ALT显著性降低；Oatp1a1，Oatp1b2及MRP2的mRNA表达水平明显下降(P<005)，但未见二者与LPS的协同作用。综上首乌藤及其提取物对胆红素相关转运体功能的抑制作用，可能是其是否造成肝损伤的原因之一。
[关键词]首乌藤； 胆红素； 转运体； 特異质； 肝毒性
Study on mechanism of hepatotoxicity of Ploygoni Multiflori Caulis based on
, http://www.100md.com
function inhibition of bilirubinassociated transporters in idiosyncratic rat
LI Hongpin1， ZHU Hongyu1， GAO Xing1， MA Pengkai1， CHEN Jianhua1， BI Xinning1， WANG Qi2*， ZHANG Yujie1*
(1. School of Chinese Materia Medica， Beijing University of Chinese Medicine， Beijing 100102， China；
2. National Institute for Food and Drug Control， Beijing 100050， China)
[Abstract]To explore the possible mechanism of liver injury， the effects of Ploygoni Multiflori Caulis and its extractive on the function of bilirubinassociated transporters were investigated in normal (N) and idiosyncratic (LPS) rats (M) The normal and LPS rats were respectively administrated powder of Ploygoni Multiflori Caulis， its extractive and same volume of 05% CMCNa solution for 7 d BSP， a substrate of the transporters of Oatp1a1 and Oatp1b2 was selected， and its pharmacokinetic parameters of intravenous injection were determined to examined the activity these transporters Meanwhile the mRNA expressions of transporters were detected Compared with Nblank control group， besides Mpowder group， the Cmax has no significantly different from other groups， t1/2， AUC0t and AUC0∞ were significantly increased， and CL were significantly decreased However， compared with N blank control group， AST and ALT decreased significantly The expression of Oatp1a1， Oatp1b2 and MRP2 mRNA was significantly decreased (P<005)， but there was no act synergistically when Ploygoni Multiflori Caulis and extractive were combined with LPS The function of Oatp1a1， Oatp1b2 and MRP2 in rats were significantly inhibited by Ploygoni Multiflori Caulis and extractive， which may be an important cause of hepatotoxicity.
, 百拇医药
[Key words]Ploygoni Multiflori Caulis； bilirubin； transporter； idiosyncratic； hepatotoxicity
首乌藤Ploygoni Multiflori Caulis为蓼科植物何首乌Polygonum multiflorum Thunb的干燥藤茎，用于失眠多梦，血虚身痛等[1]。所含化学成分与何首乌类似，主要为蒽醌类、二苯乙烯苷、鞣质和二蒽酮等几类化合物[2]。近年来首乌藤肝毒性作用逐渐被发现，引起各界的关注，但其毒性物质成分及肝损伤机制尚不明了。
临床上，首乌藤的毒性症状主要表现为胆管上皮细胞受损，肝细胞功能紊乱及胆汁瘀积 [34]。胆红素作为胆汁的主要成分，有结合胆红素(BG)和非结合胆红素(UCB)之分，生理浓度的UCB具有抗氧化活性，高浓度则容易产生细胞毒性，是胆汁瘀积性肝损伤的重要原因。血液中的UCB主要通过转运体Oatp1b1和Oatp1b3(大鼠为Oatp1a1和Oatp1b2)摄取入肝脏，在肝脏中经过代谢酶作用成为BG，再经转运体MRP2外排致胆汁中。若胆红素相关代谢酶或转运体的功能出现障碍，都将导致UCB在肝细胞和血液内蓄积，引发肝毒性，产生黄疸[5]。为此有人推测何首乌可能具有抑制胆红素(胆汁酸)相关转运体的作用，从而造成胆红素转运肝细胞受阻，进而形成瘀积，使肝组织受损。目前这一推论已在体外细胞模型上获得证实[6]，研究表明何首乌中的多种化学成分对胆汁酸转运体存在抑制作用。由于转运体在体内较之体外所受影响因素的复杂性，以及体内多种代偿调控作用的客观存在，体外结果不能完全反映何首乌对转运体的实际作用情况，体内验证实验研究是十分必要的。此外，最近王伽伯等[7]通过大数据分析，发现何首乌及其制剂所致肝损伤的总体发病率较低，可能存在高危人群，类似于特异质性肝损伤。并且目前对于首乌藤缺乏研究。, http://www.100md.com(李红品朱虹宇高兴马鹏凯陈建华毕欣宁汪祺张玉杰)
[关键词]首乌藤； 胆红素； 转运体； 特異质； 肝毒性
Study on mechanism of hepatotoxicity of Ploygoni Multiflori Caulis based on
, http://www.100md.com
function inhibition of bilirubinassociated transporters in idiosyncratic rat
LI Hongpin1， ZHU Hongyu1， GAO Xing1， MA Pengkai1， CHEN Jianhua1， BI Xinning1， WANG Qi2*， ZHANG Yujie1*
(1. School of Chinese Materia Medica， Beijing University of Chinese Medicine， Beijing 100102， China；
2. National Institute for Food and Drug Control， Beijing 100050， China)
[Abstract]To explore the possible mechanism of liver injury， the effects of Ploygoni Multiflori Caulis and its extractive on the function of bilirubinassociated transporters were investigated in normal (N) and idiosyncratic (LPS) rats (M) The normal and LPS rats were respectively administrated powder of Ploygoni Multiflori Caulis， its extractive and same volume of 05% CMCNa solution for 7 d BSP， a substrate of the transporters of Oatp1a1 and Oatp1b2 was selected， and its pharmacokinetic parameters of intravenous injection were determined to examined the activity these transporters Meanwhile the mRNA expressions of transporters were detected Compared with Nblank control group， besides Mpowder group， the Cmax has no significantly different from other groups， t1/2， AUC0t and AUC0∞ were significantly increased， and CL were significantly decreased However， compared with N blank control group， AST and ALT decreased significantly The expression of Oatp1a1， Oatp1b2 and MRP2 mRNA was significantly decreased (P<005)， but there was no act synergistically when Ploygoni Multiflori Caulis and extractive were combined with LPS The function of Oatp1a1， Oatp1b2 and MRP2 in rats were significantly inhibited by Ploygoni Multiflori Caulis and extractive， which may be an important cause of hepatotoxicity.
, 百拇医药
[Key words]Ploygoni Multiflori Caulis； bilirubin； transporter； idiosyncratic； hepatotoxicity
首乌藤Ploygoni Multiflori Caulis为蓼科植物何首乌Polygonum multiflorum Thunb的干燥藤茎，用于失眠多梦，血虚身痛等[1]。所含化学成分与何首乌类似，主要为蒽醌类、二苯乙烯苷、鞣质和二蒽酮等几类化合物[2]。近年来首乌藤肝毒性作用逐渐被发现，引起各界的关注，但其毒性物质成分及肝损伤机制尚不明了。
临床上，首乌藤的毒性症状主要表现为胆管上皮细胞受损，肝细胞功能紊乱及胆汁瘀积 [34]。胆红素作为胆汁的主要成分，有结合胆红素(BG)和非结合胆红素(UCB)之分，生理浓度的UCB具有抗氧化活性，高浓度则容易产生细胞毒性，是胆汁瘀积性肝损伤的重要原因。血液中的UCB主要通过转运体Oatp1b1和Oatp1b3(大鼠为Oatp1a1和Oatp1b2)摄取入肝脏，在肝脏中经过代谢酶作用成为BG，再经转运体MRP2外排致胆汁中。若胆红素相关代谢酶或转运体的功能出现障碍，都将导致UCB在肝细胞和血液内蓄积，引发肝毒性，产生黄疸[5]。为此有人推测何首乌可能具有抑制胆红素(胆汁酸)相关转运体的作用，从而造成胆红素转运肝细胞受阻，进而形成瘀积，使肝组织受损。目前这一推论已在体外细胞模型上获得证实[6]，研究表明何首乌中的多种化学成分对胆汁酸转运体存在抑制作用。由于转运体在体内较之体外所受影响因素的复杂性，以及体内多种代偿调控作用的客观存在，体外结果不能完全反映何首乌对转运体的实际作用情况，体内验证实验研究是十分必要的。此外，最近王伽伯等[7]通过大数据分析，发现何首乌及其制剂所致肝损伤的总体发病率较低，可能存在高危人群，类似于特异质性肝损伤。并且目前对于首乌藤缺乏研究。, http://www.100md.com(李红品朱虹宇高兴马鹏凯陈建华毕欣宁汪祺张玉杰)