川芎嗪诱导小鼠肝药酶Cyp3a11的作用及其机制研究

Effect and Mechanism of Ligustrazine Induced Liver Drug Metabolism Enzyme Cyp3a11

关键词:  川芎嗪  药物相互作用  CYP3A4  Cyp3a11

Key words:  ligustrazine  drug-drug interactions  CYP3A4  Cyp3a11

摘要:

目的 考察川芎嗪对小鼠肝药物代谢酶Cyp3a11（CYP3A4同源基因）的作用及相关机制。方法 24只8周龄C57BL/6小鼠随机分为对照组和川芎嗪低、中、高剂量（25，50，100 mg·kg^-1）组，连续灌胃给药15 d。以RT-PCR法检测肝脏Cyp3a11 mRNA表达。采用差速离心法提取肝微粒体，以Cyp3a11经典底物咪达唑仑进行孵育，HPLC-MS/MS检测肝脏Cyp3a11活性。以双荧光报告基因法分析川芎嗪对CYP3A4转录活性的影响。结果 川芎嗪可诱导小鼠肝脏中Cyp3a11的mRNA表达，且诱导作用呈剂量依赖性增加。高剂量组可诱导Cyp3a11的代谢活性升高。川芎嗪可通过核受体PXR途径激活CYP3A4启动子转录活性。结论 川芎嗪对CYP3A4同源基因Cyp3a11的表达和活性具有一定的诱导作用，提示在临床使用过程中可能存在潜在的药物相互作用风险。

Abstract:

OBJECTIVE To investigate the role and mechanism of ligustrazine in mice liver drug metabolism enzyme Cyp3a11 (CYP3A4 homologous gene). METHODS Eight-week-old male C57BL/6 mice were treated oridonin orally (0, 25, 50, 100 mg·kg^-1, i.g.) for 15 d. The effects of oridonin on Cyp3a11 in mice livers were examined at both the mRNA and enzyme activity levels, which detected by RT-PCR and HPLC-MS/MS respectively. Finally, the effect of ligustrazine on the transcription activity of CYP3A4 was analyzed by luciferase reporter gene assays. RESULTS Ligustrazine could induce the mRNA expression of Cyp3a11 in mice and the induction were dose-dependently. At the same time, the liver microsomal activity experiment showed that the metabolic activity of Cyp3a11 was increased in high dose group. The results showed of luciferase reporter gene assays that ligustrazine activated CYP3A4 promoter transcriptional activity through nuclear receptor PXR pathway. CONCLUSION Ligustrazine could induce the expression and activity of Cyp3a11, homologous gene of CYP3A4. Since ligustrazine is usually co-administered with other clinical medicine, the present study may provide at least part of the basis for drug-drug interactions.