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The drug-induced hepatotoxicity

药物引起的肝毒性

基本信息

批准号：
09470491
负责人：
HORIE Toshiharu
金额：
$ 5.95万
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：
1997
资助国家：
日本
起止时间：
1997 至 1999
项目状态：
已结题

项目摘要

The drug-induced hepatotoxicity was studied on the oxidative stress and reactive metabolites, using liver microsomes, isolated hepatocytes, primary cultured hepatocytes and liver tissues.The chemiluminescence was used to investigate the drug-induced oxidative stress. The chemiluminescence-HPLC system was set up and we tried to measure the lipid peroxides produced during the drug metabolism. And phosphatidyl choline hydroperoxide (PCOOH) was detected in the rat liver microsome and isolated hepatocyte suspension incubated with ethacrynic acid. It was observed that PCOOH was produced earlier than the thiobarbituric acid reactive substances (TBARS) formation. The ultraweak chemiluminescence was shown to be emitted directly from the liver microsomes and isolated hepatocytes incubated with ethacrynic acid. This was accompanied by the LDH release from the isolated hepatocytes. Further, we set up the organ chemiluminescence system and succeeded in detecting the ultraweak chemiluminescence emitted from the rat liver perfused with ethacrynic acid. This result substantiated the ethacrynic acid-induced oxidative stress in the liver. These results obtained from the chemiluminescence detection systems were found to be related closely with the alteration in glutathione. Thus the oxidative stress due to the drug metabolism was shown to be detectable by the chemiluminescence system with high sensitivity and specificity.Dihydralazine is known to cause the immunohepatitis and CYP1A2 is reported as a target protein of its reactive metabolite. In addition, CYP3A4 was found to be its target protein in rat and human liver microsomes. The imipramine- and mianserin-induced hepatotoxicity was shown to be closely related with their reactive metabolites. The diphenylamine structure was found to play an important role in the nonsteroidal anti-inflammatory drug-induced hepatotoxicity. The NSAIDs with diphenylamine structure were shown to be uncouplers of oxidative phosphorylation.

采用肝微粒体、分离肝细胞、原代培养肝细胞和肝组织，从氧化应激和反应性代谢产物方面研究药物引起的肝毒性。采用化学发光法研究药物引起的氧化应激。建立了化学发光-HPLC系统，尝试测定药物代谢过程中产生的脂质过氧化物。在与利尿酸孵育的大鼠肝微粒体和分离的肝细胞悬液中检测到磷脂酰胆碱过氧化氢(PCOOH)。据观察，PCOOH 的产生早于硫代巴比妥酸反应物质 (TBARS) 的形成。超弱化学发光被证明是直接从与利尿酸一起孵育的肝微粒体和分离的肝细胞中发射的。这伴随着分离的肝细胞中 LDH 的释放。此外，我们建立了器官化学发光系统，并成功检测到了灌注利尿酸的大鼠肝脏发出的超弱化学发光。这一结果证实了利尿酸诱导的肝脏氧化应激。化学发光检测系统获得的这些结果被发现与谷胱甘肽的变化密切相关。因此，化学发光系统可以高灵敏度和特异性地检测药物代谢引起的氧化应激。已知二肼苯达嗪会引起免疫性肝炎，据报道CYP1A2是其反应性代谢物的靶蛋白。此外，在大鼠和人肝微粒体中发现CYP3A4是其靶蛋白。丙咪嗪和米安舍林引起的肝毒性与其活性代谢物密切相关。研究发现二苯胺结构在非甾体抗炎药引起的肝毒性中发挥重要作用。具有二苯胺结构的非甾体抗炎药被证明是氧化磷酸化的解偶联剂。