Reversing effects of lignans on CCl4-induced hepatic CYP450 down regulation by attenuating oxidative stress
Reversing effects of lignans on CCl4-induced hepatic CYP450 down regulation by attenuating oxidative stress
复制标题
通过减弱氧化应激，逆转木脂素对 CCl4 诱导的肝脏 CYP450 下调的影响。
DOI：
10.1016/j.jep.2014.05.016
复制
发表时间：
2014-08-08
影响因子：
5.4
通讯作者：
Wang, Guangji
中科院分区：
文献类型：
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作者：
Xie, Yuan;Hao, Haiping;Wang, Guangji
氧化应激已被证实是肝损伤状态下CYP 450调节的重要原因。研究五味子木脂素提取物（SLE）和联苯二甲酸二甲酯（DDB）预处理对四氯化碳（CCl 4）诱导的肝损伤大鼠肝脏主要P450同工酶表达和活性的影响，以及对四氯化碳诱导的肝损伤大鼠和HepG 2细胞损伤模型的抗氧化作用。CCl_4诱导的急性实验性肝损伤可引起肝脏主要P450同工酶如CYP 1A 2、CYP 2C 6、CYP 2 E1和CYP 3A 2的活性及其蛋白表达的显著降低。预先给予SLE（500 mg/kg）和DDB（200 mg/kg），每日2次，连续3 d，可显著降低CYP 1A 2、CYP 2C 6、CYP 2 E1和CYP 3A 2的活性损失。在蛋白质表达中观察到类似的结果。此外，在CCl 4诱导的HepG 2细胞损伤模型中，SLE各成分治疗组中CYP 3A活性水平与ROS水平均呈良好的相关性，其中以五味子甲素组最为显著。这些结果表明，SLE/DDB治疗后P450的逆转一方面是由于这些木脂素对肝脏的保护作用，另一方面是由于它们通过抗氧化作用调节P450，7-五味子醇甲可能是SLE最有效的成分。此外，SLE或DDB与联合用药之间可能存在潜在的相互作用，在肝病临床用药中有必要调整联合用药的剂量。(C)由Elsevier爱尔兰Ltd.出版
Oxidative stress has been proved to be a critical reason of regulating CYP450s under hepatic injury status. The study was aimed to investigate the effect of pretreatment of schisandra lignan extracts (SLE) and dimethyl diphenyl bicarboxylate (DDB) on expressions and activities of the main liver P450 isoenzymes in CCl4 induced liver injury rats and their anti-oxidative effects on both CCl4 induced liver injury rats and a CCl4 induced HepG2 cell injury model. Acute experimental liver injury induced by CCl4 caused drastically decreasing activities of the main liver P450 isoenzymes such as CYP1A2, CYP2C6, CYP2E1 and CYP3A2, as well as their protein expressions. Pretreatment of SLE (500 mg/kg) and DDB (200 mg/kg) twice a day for three days significantly decreased the losses of activities of CYP1A2, CYP2C6, CYP2E1 and CYP3A2. Similar results were observed in protein expressions. In addition, in the CCl4 induced HepG2 cells injury model and the CYP3A activity level correlated well with ROS level in several ingredients of SLE treated groups, especially in gamma-schisandrin group. These results indicated that the reversion of P450 after SLE/DDB treatment were, on one hand, due to hepatoprotective effects of these lignans on livers; on the other hand, due to their regulation of P450 through anti-oxidative effect and 7-schisandrin might be the most powerful ingredient of SLE. Also, there might be potential interactions between SLE or DDB and co-administered medicines and it is necessary to adjust the dosage of co-administrated medicines in clinical medication of liver disease. (C) 2014 Published by Elsevier Ireland Ltd.