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目的:在体外研究ABCB1(1199G>A)基因多态性对多西他赛转运影响的分子机制。方法:将ABCB1(1199G>A)野生型和突变型基因分别导入HEK293细胞,研究2种重组细胞株对多西他赛的摄取以及跨膜转运的差异。结果:在细胞毒性分析中,ABCB1_(1199A/mut)细胞对多西他赛表现出更强的耐药性。多西他赛在2种重组细胞中的含量均显著性的低于对照组细胞,证实了多西他赛是由P-糖蛋白介导转运的,并且在ABCB1_(1199A/mut)细胞中跨膜转运更高。ABCB11199A/mut细胞介导转运多西他赛的P-糖蛋白的活性较ABCB1_(1199G/wt)细胞的更强。结论:ABCB1(1199G>A)基因多态性能够显著性影响P-糖蛋白转运多西他赛的能力,由ABCB1突变型基因编码的P-糖蛋白能够更有效的转运多西他赛。因此ABCB1(1199G>A)基因多态性可能会影响P-糖蛋白的活性,并对药物的分布和消除产生影响,从而影响药物的治疗作用。
OBJECTIVE: To study the molecular mechanism of ABCB1 (1199G> A) polymorphism on docetaxel transport in vitro. Methods: The wild type and mutant type of ABCB1 (1199G> A) were respectively introduced into HEK293 cells to study the difference of uptake and transmembrane transport of docetaxel between two recombinant cell lines. Results: ABCB1_ (1199A / mut) cells showed more resistance to docetaxel in cytotoxicity assays. Docetaxel was significantly lower in both recombinant cells than in control cells, confirming that docetaxel is mediated by P-glycoprotein and that in ABCB1_ (1199A / mut) cells, Membrane transport is higher. ABCB11199A / mut cells were more potent than ABCB1_ (1199G / wt) cells for the transport of docetaxel. CONCLUSION: ABCB1 (1199G> A) gene polymorphism can significantly affect the ability of P-glycoprotein to transport docetaxel. P-glycoprotein encoded by the ABCB1 mutant gene can deliver docetaxel more effectively. Therefore, ABCB1 (1199G> A) gene polymorphism may affect the activity of P-glycoprotein and affect the distribution and elimination of the drug, thus affecting the therapeutic effect of the drug.