- 學位論文
探討flavonoids調節P-glycoprotein引起的多重抗藥性之研究
Modulation of Flavonoids on P-glycoprotein-mediated Multidrug Resistance
摘要
Flavonoids是植物的二次代謝多酚化合產物，富含在現代人的日常飲食中，包括蔬果和中草藥，一般認為flavonoids的抗氧化、抗病毒、和抗癌能力可促進人類健康。此外，研究指出Flavonoids會與腸道的運輸蛋白產生交互作用，尤其是P-glycoprotein (P-gp)。P-gp是一種廣泛存在於人體中具有170-kDa的運輸蛋白，而P-gp的過度表現和腫瘤細胞的抗藥性 (MDR) 有密切的關係。利用中草藥成分抑制P-gp作用，改變腫瘤細胞的多重抗藥性為一新穎的研究。本研究之體外試驗，利用人類腸道腺癌細胞 (HCT-15 cells)，以fexofenadine作為P-gp受質藥物，分析flavones、flavonols、flavanols和isoflavones四種類的flavonoids成分，探討此四類flavonoids成分對於P-gp活性抑制之能力，並藉由此實驗討論flavonoids結構與抑制P-gp活性能力的關係。體外試驗發現galangin、apigenin和baicalein具有高度抑制P-gp活性的能力，並歸納出flavonoids結構上的OH基數量、立體結構以及疏水性為影響flavonoids抑制P-gp活性能力的因子。本研究之體內試驗，實驗動物兔子併服baicalein和fexofenadine，baicalein會經由抑制P-gp而明顯地增加fexofenadine的生體可用率。因此，flavonoids確實會與P-gp受質藥物產生交互作用，而baicalein可能為一有潛力的可改變多重抗藥性之調控劑。
並列摘要
Flavonoids are a subclass of dietary polyphenolic compounds present in fruits, vegetables, and herbal plants and are proposed to promote human health by their antioxidant, antiviral, or anticarcinogenic properties. They are suggested to interact with intestinal transport systems including P-glycoprotein (P-gp). Overexpression of the 170-kDa P-gp has been associated with the multidrug resistance (MDR) of cancer cells. The inhibition of P-gp by herbal constituents may provide a novel approach for reversing multidrug resistance in tumor cells. Using human colorectal adenocarcinoma (HCT15) cells as an in vitro model and fexofenadine as a P-gp substrate, four flavonoid families (flavones, flavonols, flavanols, and isoflavones) were evaluated for their inhibitory effects on P-gp to create a structure-activity relationship (SAR). The in vitro data show that galangin, apigenin, and baicalein possess high inhibitory effect on P-gp activity. We may conclude from our results that the number of hydroxyl groups, dimensional structure, and the hydrophobicity of flavonoids play significant influences on their inhibitory effects. The bioavailability of fexofenadine in the rabbits co-administration with baicalein, which inhibits the efflux pump P-gp, is increased significantly compared with the control. The findings of this study indicate potential flavonoids-drug interactions with P-gp substrates. Furthermore, baicalein could be a useful strategy for the development of potential modulators and a promising reversal agent for overcoming MDR.