人参、藜芦合用对大鼠肝P450酶活性及mRNA表达的调控作用

Modulation of the activities and mRNA expression of cytochrome P450 isoenzymes in rat liver by Panax gingseng and coadministration with Veratrum nigrum

目的 :研究中药十八反中人参与藜芦合用对P4 5 0同工酶在酶活性及mRNA水平的调控作用。方法 :采用紫外分光光度法测定大鼠肝微粒体细胞色素P4 5 0与细胞色素b5含量及氨基比林N 脱甲基酶 (APND)、对硝基苯酚羟化酶 (pNPH)活性。采用RT PCR技术检测大鼠肝中 5种P4 5 0同工酶CYP1A1,CYP2B1/ 2 ,CYP2C11,CYP2E1及CYP3A1mRNA的表达。结果 :人参与藜芦合用可明显降低P4 5 0蛋白含量 ,可降低细胞色素b5的含量 ,单药及其与藜芦配伍都能使APND活性下降。在mRNA水平上 ,藜芦可诱导CYP2C11的基因表达 ,与人参合用后却使得CYP2C11的表达下降。藜芦与人参配伍诱导了CYP1A1的表达。人参可抑制CYP2B1/ 2的基因表达 ,与藜芦合用后却明显诱导了CYP2B1/ 2的表达 ,人参与藜芦合用后也明显诱导了CYP3A1的表达。结论 :人参与藜芦配伍前后对一些CYP亚型调控作用发生明显变化 ,可能存在基于药物代谢酶机理的相反作用 ,需进一步结合代谢研究加以综合分析 。

Objective:To study the modulatory effect of Panax gingseng and coadministration with Veratrum nigrum on the activity and mRNA expression of cytochrome P450 isoenzymes in rat liver. Method:Rat liver microsomal cytochrome P450, b 5, aminopyrine N demethylase(APND), p nitrophenol hydroxylase( p NPH)activities were quantitated by UV chromatography. The mRNA expression level of five CYP isoenzymes CYP1A1,CYP2B1/2, CYP2C11, CYP2E1 and CYP3A1 were detected by semi quantitative reverse transcriptase polymerase chain reaction(RT PCR). Result: P. gingseng coadministrated with V. nigrum obviously decreased the P450 contents of liver microsomes, and the b 5 contents. Both single and combinined used inhibited the activities of aminopyrine N demethylase. At the mRNA level, the expression of CYP2C11 markedly induced exposure to V. nigrum , but combinative groups decreased the expression of CYP2C11. The combination of P. gingseng and V. nigrum induced the expression of CYP1A1. P. gingseng has inhibitory effect on CYP2B1/2 and inductive effect used with V. nigrum , The combination of P. gingseng with V. nigrum also induced the expression of CYP3A1. Conclusion: P. gingseng used singly has some different modulation effects compared with combinative used, which may occur because of drug drug interaction based on cytochrome P450. To elucidate the drug drug interaction, it needs further analysis and metabolism research.