柴胡总皂苷对小鼠肠道首过效应和肝脏Cyp3a、Cyp2e1的影响

摘要/Abstract

摘要： 目的: 研究柴胡总皂苷对小鼠肠道首过效应(Cyp3a, P-糖蛋白)和肝脏细胞色素氧化酶(Cyp3a, Cyp2e1)的影响。方法: 供试物灌胃给小鼠2次/d,连续3 d。实验当日,对乙酰氨基酚(Acetaminophen, APAP;P-gp底物)以50 mg/kg经口投予后60 min断头采血,并摘取肝脏和全段小肠。以分光光度法测定血中APAP浓度;用梯度离心法分离小鼠肝/肠微粒体;以分光光度法检测微粒体中Cyp3a/Cyp2e1活性;以实时荧光定量法测定Cyp3a11/Cyp2e1 mRNA在小鼠肝脏中的表达。结果: 血中APAP浓度测定结果和P-糖蛋白偶联的ATP酶活性测定结果显示,柴胡总皂苷各剂量组与对照组之间均无统计学差异(P>0.05);在肝脏和肠道微粒体实验中不论以氨基吡啉还是以红霉素为底物测定Cyp3a,仅有柴胡总皂苷高剂量组(150 mg/kg)的Cyp3a活性显著高于对照组(P<0.05);仅有柴胡总皂苷中剂量组(75 mg/kg)的Cyp2e1活性显著低于对照组(P<0.05);RT-PCR结果显示,仅有柴胡总皂苷高剂量(150 mg/kg)时能够诱导Cyp3a11在肝脏中的表达。结论: 柴胡总皂苷对小鼠肝脏和肠道中的Cyp3a具有一定的诱导作用,对肝脏中的Cyp2e1具有一定的抑制作用,对小鼠肠道P-糖蛋白的转运活性无影响。

关键词: 柴胡总皂苷, Cyp3a11, Cyp2e1, P-糖蛋白, mRNA表达

Abstract: AIM: To investigate the effect of total saikosaponins on intestinal first-pass effect (Cyp3a, P-glycoprotein) and Cytochrome P450 (Cyp3a, Cyp2e1).METHODS: The mice of each group were treated with water or investigated samples at two times a day for three days. The concentration of acetaminophen was determined by spectrophotometer. Liver/intestinal microsomes were separated by ultracentrifugation. The activity of Cyp3a and Cyp2e1 was detected by spectrophotometry. The expression of Cyp3a11/Cyp2e1 mRNA in liver was estimated by real-time PCR.RESULTS: Blood APAP concentration and P-glycoprotein coupled ATPase activities were no significant differences between all saikosaponin groups and control group (P>0.05); Cyp3a activities of high-dosage group (150 mg/kg) both in liver and intestinal microsomes, erythromycin and aminopyrine as the substrate, was significantly higher than that of control group (P<0.05) in both intestine and liver, Cyp2e1 activity of liver microsomes in high-dosage group (150 mg/kg) was significantly lower than that of control group (P<0.05); RT-PCR results indicate that only high doses of saikosaponins (150 mg/kg) can induce the expression of Cyp3a11 in the liver.CONCLUSION: Total saikosaponins can induce CYP3A4 activity in mouse liver and intestine, while inhibit Cyp2e1 activity in mouse liver and have no influence on P-glycoprotein efflux activity when large dosage was administrated.

Key words: Saikosaponins, Cyp3a11, Cyp2e1, P-glycoprotein, mRNA expression

中图分类号:

R965.2

王永辉, 奇锦峰, 林梅. 柴胡总皂苷对小鼠肠道首过效应和肝脏Cyp3a、Cyp2e1的影响[J]. 中国临床药理学与治疗学, 2011, 16(7): 740-748.

WANG Yong-hui, QI Jin-feng, LIN Mei. Effect of total saikosaponins on the intestinal first-pass effect and liver Cyp3a, Cyp2e1[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2011, 16(7): 740-748.

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