ABCB1(1199G>A)基因多态性对多西他赛转运影响的分子机制

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。ABCB1_1199A/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。

Molecular mechanism of effects of ABCB1 (1199G>A) gene polymorphism on docetaxel transportation

OBJECTIVE To study molecular mechanism of effects of ABCB1 (1199G>A) gene polymorphism on docetaxel transportation in vitro. METHODS ABCB1 genes carrying wild type allele (1199G) and its variant counterpart (1199A) were transfected into human embryonic kidney (HEK293) cell lines. Impact of 1199G>A single nucleotide polymorphism (SNP) were evaluated on these compounds accumulation, transepithelial permeability and P-gp activity towards drugs. RESULTS Recombinant ABCB1_1199A/mut cells displayed higher resistance to docetaxel compared to cells transfected ABCB1_1199G/wt in cytotoxicity assay. Docetaxel accumulation was strongly decreased in cells transfected ABCB1 allele in comparison to control cells, confirming the ability of P-gp-mediated docetaxel efflux. ABCB1_1199A/mut cells seemed to be more efficient for efflux of docetaxel than wild type cells. Transepithelial permeability of docetaxel in ABCB1_1199A/mut cells were greater than cells expressing ABCB1 wild type allele. P-gp activity in recombinant variant cells was stronger when mediated efflux of docetaxel than wild-type counterpart. CONCLUSION P-gp encoded by ABCB1 variant allele may be more efficient to transport docetaxel when compared to wild type allele. ABCB1 1199G>A single nucleotide polymorphism (SNP) drastically affects the ability of P-gp to transport efflux of docetaxel. Overall, ABCB1 1199G>A polymorphism may influence P-gp activity and drug efficacy through regulation of drug distribution and delivery.