The role of Ntcp, Oatp2, Bsep and Mrp2 in liver injury induced by Dioscorea bulbifera L. and Diosbulbin B in mice
The role of Ntcp, Oatp2, Bsep and Mrp2 in liver injury induced by Dioscorea bulbifera L. and Diosbulbin B in mice
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DOI：
10.1016/j.etap.2017.02.023
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发表时间：
2017-04-01
影响因子：
4.3
通讯作者：
Song, Yan-Qing
中科院分区：
文献类型：
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作者：
Qu, Xiao-Yu;Tao, Li-Na;Song, Yan-Qing
山药是一种治疗甲状腺疾病和癌症的传统中草药。然而，DB的临床应用仍然是一个挑战，因为它的肝脏毒性，这在一定程度上是由山药苷B(Diob)的存在引起的，Diob是一种在DB提取物中常见的毒素。鉴于肝胆转运蛋白的异常表达在药物性肝损伤中起着重要作用，我们评估了DB和Diob的肝毒性，并探讨了它们对肝胆转运蛋白表达水平的影响。用高效液相色谱-串联质谱联用技术分析DB提取物中Diob的含量后，随机给雄性ICR小鼠灌胃DB或Diob，共14天。通过组织病理学和肝功能生化分析评价肝损伤程度。Western blotting和实时荧光定量聚合酶链式反应(Real-time PCR)检测转运蛋白和信使核糖核酸水平。肝功能和组织病理学分析表明，DB和Diob均可引起小鼠肝损伤，且Diob可能是DB的主要毒性物质。此外，MRP2的下调阻止了胆红素、谷胱甘肽二硫化物和胆汁酸的排泄，导致有毒底物在肝脏中积累，并导致氧化还原失衡。我们发现，MRP2的表达下调是与血清胆红素水平升高、肝脏谷胱甘肽水平降低和肝脏损伤严重程度相关的潜在因素。总之，我们的研究表明，MRP2的下调代表了DB和Diob诱导的肝毒性的主要机制，并为预防DB和Diob介导的肝损伤的新疗法提供了洞察力。(C)2017爱思唯尔B.V.保留所有权利。
Dioscorea bulbifera L. (DB) is a traditional Chinese herb used in thyroid disease and cancer. However, the clinical use of DB remains a challenge due to its hepatotoxicity, which is caused, in part, by the presence of Diosbulbin B (DIOB), a toxin commonly found in DB extracts. As abnormatexpression of hepatobiliary transporters plays an important role in drug-induced liver injury, we assessed the hepatotoxicity induced by DB and DIOB, and explored their impacts on hepatobiliary transporter expression levels. Following liquid chromatography-tandem mass analysis of the DIOB content of DB extract, male ICR mice were randomly orally administered DB or DIOB for 14 days. Liver injury was assessed by histopathological and biochemical analysis of liver fuction. The levels of transporter protein and mRNA were determined by western blotting and real-time PCR. Liver function and histopathological analysis indicated that both DB and DIOB could induce liver injury in mice, and that DIOB might be the primary toxic compound in DB. Moreover, down-regulation of Mrp2 blocked the excretion of bilirubin, glutathione disulfide, and bile acids, leading to the accumulation of toxic substrates in the liver and a redox imbalance. We identified down-regulated expression of Mrp2 as potential factors linked to increased serum bilirubin levels and decreased levels of glutathione in the liver and increased liver injury severity. In summary, our study indicates that down-regulation of Mrp2 represents the primary mechanism of DB- and DIOB-induced hepatotoxicity, and provides insight into novel therapies that could be used to prevent DB- and DIOB-mediated liver injury. (C) 2017 Elsevier B.V. All rights reserved.