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目的研究9种黄酮类化合物和5种芪类化合物对血脑屏障上P-糖蛋白(P-gp)外排沙奎那韦的影响。方法以过表达P-gp的马丁达比犬肾上皮细胞(MDCKII-MDR1)作为血脑屏障体外模型。药物干预分为16组(n=4),包括阴性对照组、阳性对照组、黄酮类实验I-IX组和芪类实验组Ⅰ-Ⅴ组。药物干预分别为50μmol·L~(-1)沙奎那韦(阴性对照组);50μmol·L~(-1)沙奎那韦联用50μmol·L~(-1)维拉帕米(阳性对照组);50μmol·L~(-1)沙奎那韦联用25μmol·L~(-1)黄酮类(黄酮类实验I-IX组)或联用25μmol·L~(-1)芪类化合物(芪类实验组Ⅰ-Ⅴ组)。药物干预时间均为4 h。用液相色谱质谱联用技术测定沙奎那韦在各组细胞内的积聚量。结果细胞内沙奎那韦积聚量:与阴性对照组(101.46±22.00)ng·mg~(-1)相比,柚皮素组(229.41±74.86)ng·mg~(-1)、桑黄素组(149.89±30.38)ng·mg~(-1)、白杨黄素组(209.75±65.35)ng·mg~(-1)、氧化白藜芦醇组(178.54±44.40)ng·mg~(-1)、染料木黄酮组(294.49±66.35)ng·mg~(-1)、表儿茶素组(212.27±49.70)ng·mg~(-1)、三乙酰白藜芦醇组(290.94±45.54)ng·mg~(-1)和白藜芦醇三甲醚组(205.55±35.16)ng·mg~(-1),均显著升高,差异有统计学意义(P<0.05);异槲皮苷组(61.98±11.02)ng·mg~(-1)、槲皮素组(41.54±4.92)ng·mg~(-1)和白藜芦醇组(29.59±4.61)ng·mg~(-1)细胞内沙奎那韦积聚量,均显著降低,差异有统计学意义(P<0.05)。结论一些黄酮类、芪类化合物可能对P-gp介导的沙奎那韦在血脑屏障上的转运过程产生调节作用。
Objective To study the effects of 9 flavonoids and 5 stilbenes on the efflux of P-glycoprotein (P-gp) on the blood-brain barrier. Methods MDCKII-MDR1 was used as an in vitro model of BBB in which P-gp was over-expressed. Drug interventions were divided into 16 groups (n = 4), including negative control group, positive control group, flavonoids experimental I-IX group and stilbene experimental group I-V group. Drug intervention was 50μmol·L -1 saquinavir (negative control group); 50μmol·L -1 saquinavir combined with 50μmol·L -1 verapamil (positive Control group); 50μmol·L -1 saquinavir combined with 25μmol·L -1 flavonoids (flavonoids group I-IX) or 25μmol·L -1 stilbene Compound (stilbene experimental group Ⅰ-Ⅴ group). Drug intervention time are 4 h. The concentration of saquinavir in each group of cells was determined by liquid chromatography-mass spectrometry. Results The amount of saquinavir in the cells was significantly higher than that in the negative control group (101.46 ± 22.00) ng · mg ~ (-1) (229.41 ± 74.86 ng · mg -1, Phellinus linteus (149.89 ± 30.38) ng · mg -1, 209.75 ± 65.35 ng · mg -1, and 178.54 ± 44.40 ng · mg -1 in resveratrol group -1), genistein group (294.49 ± 66.35) ng · mg -1, epicatechin group (212.27 ± 49.70 ng · mg -1), triacetyl resveratrol group (290.94 ± 45.54 ng · mg ~ (-1)) and resveratrol (205.55 ± 35.16 ng · mg ~ (-1)), both of which were significantly increased (P <0.05) (61.98 ± 11.02) ng · mg ~ (-1), quercetin (41.54 ± 4.92) ng · mg ~ (-1) and resveratrol (29.59 ± 4.61) ng · mg ~ (-1) intracellular saquinavir accumulation, were significantly lower, the difference was statistically significant (P <0.05). Conclusion Some flavonoids and stilbenes may regulate the P-gp-mediated transport of saquinavir on the blood-brain barrier.