谷胱甘肽反应性代谢物引起药物性肝损伤的机制研究进展

发布时间：2018-08-04 13:25

【摘要】：目的:了解以谷胱甘肽捕获反应性代谢物研究药物肝损伤的机制,为临床安全、合理用药提供一定的理论依据。方法:以"谷胱甘肽""反应性代谢物""药物性肝损伤""Reactive metabolites""Glutathione conjugate""Liver injury"等为关键词,组合查询1993年1月-2016年4月在Pub Med、Science Direct、Web of Science、中国知网、万方、维普等数据库中的相关文献,对引起药物性肝损伤的可能机制、化学药物和中药的肝损伤研究、谷胱甘肽反应性代谢物的检测及其研究实例等方面进行综述。结果与结论:共检索到相关文献112篇,其中有效文献37篇。引起药物性肝损伤由基于细胞色素P450酶代谢、钙离子平衡破坏与细胞膜损伤、胆汁淤积与胆小管受损、自身免疫激活、线粒体功能障碍导致肝细胞凋亡等多种因素造成。对乙酰氨基酚、小檗胺、莫沙必利、去甲阿佐昔芬等单一成分的化学药物经肝脏代谢后可产生反应性代谢物,引起肝脏的毒副作用。溴芬酸、乙溴替丁、氯丙嗪、他克林、曲格列酮、曲伐沙星等化学药物因导致肝损伤而最终撤市。有100多种中草药和30多种中成药可引起药源性肝损伤。马兜铃酸、吡咯里西啶类生物碱、异喹啉类生物碱等药用植物来源单体成分的毒性已被认为与其生成反应性代谢物有关。还原型谷胱甘肽作为捕获剂,与多种反应性代谢物(Michael受体、环氧化物、芳烃环氧化物、卤代烃等)形成的复合物可由质谱在正离子模式下以中性丢失扫描质荷比(m/z)为129及负离子模式下以前体离子扫描m/z为272检出。反应性代谢物导致体内毒性的经典例子除对乙酰氨基酚的肝毒性外,还有蝙蝠葛碱、绿原酸和奥美拉唑。结论:药物代谢酶介导的谷胱甘肽反应性代谢物的生成是引起药物性肝损伤的重要原因之一,对其进行有效地监测可在一定程度上避免药品不良反应的发生,有助于在临床上制订合理用药方案、对肝损伤进行早期检测预警。
[Abstract]:Aim: to study the mechanism of drug liver injury by capturing reactive metabolites of glutathione, and to provide a theoretical basis for clinical safety and rational use of drugs. Methods: using "glutathione", "reactive metabolite", "drug-induced liver injury", "Reactive metabolites", "Glutathione conjugate" and "Liver injury" as keywords, the relevant literatures in Pub Medsite Direct Web of Science from January 1993 to April 2016 were collected and analyzed. The possible mechanism of drug-induced liver injury, the study of liver injury caused by chemical drugs and traditional Chinese medicine, the detection of glutathione reactive metabolites and its research examples were reviewed. Results & conclusion: a total of 112 literatures were retrieved, of which 37 were valid. Drug induced liver injury is caused by many factors, such as cytochrome P450 enzyme metabolism, calcium balance disruption and cell membrane damage, cholestasis and bile duct damage, autoimmune activation, mitochondrial dysfunction leading to hepatocyte apoptosis and so on. Paracetamol, berbamine, mosapride and norazoxifen can produce reactive metabolites after liver metabolism, causing toxic side effects of liver. Bromofenac, ethylbromotidine, chlorpromazine, tacrine, trioglitazone, travasfloxacin and other chemical drugs due to liver injury and eventually withdrawn from the market. There are more than 100 kinds of Chinese herbal medicine and 30 kinds of Chinese patent medicine can cause drug-induced liver injury. The toxicity of aristolochic acid, pyrrolidine alkaloids and isoquinoline alkaloids has been considered to be related to the formation of reactive metabolites. Reduced glutathione acts as a trapping agent with a variety of reactive metabolites (Michael receptors, epoxides, aromatic epoxides), The complexes formed by halogenated hydrocarbons can be detected by mass spectrometry with neutral loss scanning mass charge ratio (m / z) of 129 and anion mode with pre-bulk ion scanning m / z of 272 in positive ion mode. Classic examples of in vivo toxicity caused by reactive metabolites include dauricine, Lv Yuan acid, and omeprazole in addition to the hepatotoxicity of acetaminophen. Conclusion: the production of glutathione reactive metabolites mediated by drug metabolizing enzymes is one of the important causes of drug-induced liver injury, and monitoring it effectively can avoid the occurrence of adverse drug reactions to some extent. It is helpful to make rational drug use plan and early detection and early warning of liver injury in clinic.
【作者单位】：江苏康缘药业股份有限公司;中国药科大学中药学院;
【基金】：江苏省科学技术厅科技项目(No.BK20130403)
【分类号】：R575

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