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作 者 ：尚芳红,俸珊,张飞燕,陈乾,陈先进,张继芬,徐晓玉

期 刊 ：中国中药杂志 2015年 40卷 10期 页码：2030.

关键词：加味佛手散；配伍；子宫内膜异位症；P450；肝毒性；阿魏酸；川芎嗪；延胡索乙素；

Keywords:Jiawei Foshou San, compatibility, endometriosis, P450, liver toxicity, ferulic acid, ligustrazine, tetrahydropalmatine,

摘 要 ：考察加味佛手散及其不同药物组合对大鼠肝脏P450酶活性及肝细胞形态的影响。大鼠灌胃给药4周后处死,制备肝微粒体,采用肝微粒体体外孵育"鸡尾酒"法,HPLC-MS/MS法测定代谢产物,考察各受试组肝脏P450酶活性,HE染色观察用药前后肝组织病理变化。与对照组相比,加味佛手散组CYP1A2,CYP3A4的酶活性显著升高(P<0.05);阿魏酸+川芎嗪组、川芎嗪+延胡索乙素组CYP1A2,CYP2C9,CYP2D6,CYP2E1,CYP3A4的酶活性显著升高(P<0.05);川芎嗪组CYP1A2,CYP2D6,CYP2E1的酶活性显著升高(P<0.05);阿魏酸组CYP3A4的酶活性显著降低(P<0.05)。用药后阿魏酸和川芎嗪组肝细胞形态正常,延胡索乙素组肝小叶界限不清,肝细胞排列紊乱,边缘模糊,细胞核大小不均,炎细胞浸润。阿魏酸+延胡索乙素、川芎嗪+延胡索乙素、加味佛手散组有炎细胞浸润,但病理变化程度明显较延胡索乙素组轻微,其中加味佛手散组最轻。研究结果表明加味佛手散对大鼠肝脏的CYP1A2,CYP3A4的酶活性具有诱导作用,川芎嗪可能是加味佛手散对CYP1A2产生诱导作用的效应物质。配伍阿魏酸、川芎嗪后可降低延胡索乙素对大鼠肝脏的毒性作用。

Abstract:To investigate the effect of Jiawei Foshou San and its various combined administration on hepatic P450 enzyme activity and hepatocyte morphology in rats. Rats were orally administered with drugs for four weeks and then sacrificed to prepare liver microsomes. The liver microsomes were incubated with the cocktail method; The metabolites were determined with the rapid liquid chromatography with tandem mass spectrometry (LC-MS/MS) to investigate the hepatocyte P450 enzyme activity. In addition, the hepatic pathological changes were observed by using the hematoxylin and eosin (HE) staining. Compared with the control group, the enzyme activity of CYP1A2 and CYP3A4 in the Jiawei Foshou san group showed a significant rise (P<0.05); the enzyme activity of CYP1A2, CYP2C9, CYP2D6, CYP2E1 and CYP3A4 in the ferulic acid+ligustrazine group and the ligustrazine+tetrahydropalmatine group showed a significant rise (P<0.05); the enzyme activity of CYP1A2, CYP2D6 and CYP2E1 in the ligustrazine group showed a significant rise (P<0.05); the enzyme activity of CYP3A4 in the ferulic acid group showed a significant reduction (P<0.05). After the administration with various drugs, the hepatocyte morphologies in the ferulic acid group and the ligustrazine group were normal. The pathological changes were observed in the tetrahydropalmatine group, such as unclear boundary of hepatic lobules, disordered hepatic cell arrangement, blurred edge, anisokaryosis and infiltration of inflammatory cells. The ferulic acid+tetrahydropalmatine group, the ligustrazine+tetrahydropalmatine group and the Jiawei Foshou San group also showed inflammatory infiltration, but with less pathological changes, particularly the Jiawei Foshou San group. The study result shows that Jiawei Foshou San can induce the enzyme activity of CYP1A2 and CYP3A4, and ligustrazine may be the effective substance for inducing CYP1A2. Its combination with ferulic acid and ligustrazine can significantly reduce the liver toxicity of tetrahydropalmatine.

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