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Evaluation of drug-induced hepatotoxicity by chemiluminescence and the role of MRP2 in the hepatotoxicity

化学发光评价药物引起的肝毒性及MRP2在肝毒性中的作用

基本信息

批准号：
13470476
负责人：
HORIE Toshiharu
金额：
$ 7.3万
依托单位：
Chiba University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470476/
关键词：
chemiluminescence glutathione oxidative stress MRP2 4-hydroxynonenal reactive oxygens hepatotoxicity hepatocyte エタクリン酸

项目摘要

The oxidative stress is related to various diseases and drug-induced side effects. In this study, the oxidative stress caused by the drug metabolism in liver was evaluated by ultraweak chemiluminescence. Glutathione (GSH) is excreted through multidrug resistance-associated protein 2 (MKP2), suggesting the involvement of MRP2 in the oxidative stress. Therefore, the present study investigated the role of MRP2 under the oxidative stress, using in vitro, in situ and in vivo experimental systems.Lipid peroxidation was shown to occur by the oxidative metabolism of ethacrynic acid (EA) in liver. This indicated that the EA-induced oxidative stress was caused not only by the decrease of intracellular GSH induced by the formation of EA'SG conjugate but also by the oxidative metabolism of EA. Salicylic acid and chlorpropamide were found to induce the oxidative stress by their oxidative metabolism, since the ultraweak chemiluminescence was detected during their oxidative metabolism.4-Hydroxvnonena … More l (HNE) is a toxic product of lipid peroxidation. HNE-SG is a major metabolite of HNK The transport of HNE-SG in MEP2HTansfected cells and MRP2-defitient animals (EHKR) was investigated in order to clarify the contribution of MRP2 in its biliary excretion. It was shown that MRP2 played an important role in the biliary excretion of HNE-SG. We further investigated whether the HNE-induced cytotoxicity was reduced by MRP2 using MRP2-iaansfected cells, interestingly, the transfection of MRP2 enhanced the HNE-induced cytotoxicity This may possibly be due to the decrease of intracellular GSH provoked by the MKP2-mediated excretion of GSH and HNE-SG. Further, the cytotoxicity mediated by MRP2 under the oxidative stress was investigated using the in situ liver perfusion of EA. It was shown that the EA-induced hepatotoxicity and the occurrence of lipid peroxidation were markedly reduced in EHBR, compared with those of normal rats. Thus, the oxidative stress-induced cytotoxicity seems to be enhanced by MRP2. Less

氧化应激与多种疾病和药物引起的副作用有关。本研究采用超微弱化学发光法评价药物在肝脏代谢引起的氧化应激。谷胱甘肽（GSH）通过多药耐药相关蛋白2（MKP 2）排泄，表明MRP 2参与氧化应激。因此，本研究采用体外、原位和体内实验系统，研究了MRP 2在氧化应激中的作用，发现依他尼酸（ethacrynic acid，EA）在肝脏中的氧化代谢可导致脂质过氧化。这表明EA诱导的氧化应激不仅是由于EA与SG结合物的形成导致细胞内GSH含量下降所致，而且还与EA的氧化代谢有关。发现水杨酸和氯磺丙脲通过氧化代谢诱导氧化应激，因为在它们的氧化代谢过程中检测到超弱化学发光。 ...更多信息 1（HNE）是脂质过氧化的有毒产物。HNE-SG是HNK的主要代谢产物。为了阐明MRP 2在其胆汁排泄中的作用，研究了HNE-SG在MEP 2 HT转染细胞和MRP 2缺陷动物（EHKR）中的转运。MRP 2在HNE-SG的胆汁排泄中起重要作用。我们进一步研究了MRP 2是否能降低HNE诱导的细胞毒性，有趣的是，MRP 2的转染增强了HNE诱导的细胞毒性，这可能是由于MKP 2介导的GSH和HNE-SG的分泌引起的细胞内GSH的减少。此外，使用EA原位肝灌注研究了氧化应激下MRP 2介导的细胞毒性。结果表明，与正常大鼠相比，EHBR可明显减轻EA引起的肝毒性和脂质过氧化反应的发生。因此，氧化应激诱导的细胞毒性似乎被MRP 2增强。少