不同性激素对P-糖蛋白表达水平及甲磺酸伊马替尼转运的影响

目的：探讨在ABCB1（1199G/A）重组细胞模型中不同性激素对P-糖蛋白（P-gp）表达水平及甲磺酸伊马替尼转运的影响。方法：将构建的ABCB1_1199G/wt和ABCB1_1199A/mut重组质粒稳定转染入HEK293细胞中，采用RT-PCR和Western Blot分别检测不同性激素对P-gp mRNA和蛋白的表达水平；采用HPLC检测性激素对甲磺酸伊马替尼累积量的影响。结果：浓度梯度的性激素（雌酮、雌三醇雌二酮、黄体酮和睾酮）刺激ABCB1_1199G/wt 和ABCB1_1199A/mut重组细胞后，雌酮和雌三醇能刺激P-gp mRNA和蛋白表达水平，且雌三醇上调ABCB1_1199A/mut mRNA的表达水平显著高于ABCB1_1199G/wt；雌酮和雌三醇可降低甲磺酸伊马替尼在细胞内的累积量，产生对伊马替尼的耐药性。结论：雌酮和雌三醇增加了细胞内P-gp的表达，并促进P-gp介导甲磺酸伊马替尼的转运能力。

Effects of different sex hormones on P-gp expression and imatinib mesylate transport

OBJECTIVE To investigate the effect of different sex hormones on the expression of P-gp and the transport of imatinib mesylate in ABCB1 (1199G/A) recombinant cell model.METHODS The recombinant plasmids of ABCB1 (1199G/A) were stably transfected into HEK293 cells, and the expression of P-gp mRNA and protein was detected by RT-PCR and Western blot, respectively. The cumulative amount of imatinib was detected by HPLC.RESULTS The recombinant ABCB11199G/wt and ABCB11199A/mut cells were incubated with various concentrations of hormones (estrone, estradiol, estriol, progesterone and testosterone), the results of Western blot and RT-PCR showed that the expressions of P-gp protein and mRNA were stimulated by estrone or estriol. Moreover, the up-regulation of mRNA expression in ABCB11199A/mut cells by estriol was significantly higher than ABCB11199G/wt cells. Estrone and estriol could reduce the intracellular accumulation of imatinib mesylate.CONCLUSION Estrone or estriol of certain concentrations can up-regulate the expression levels of P-gp and mRNA. Estrone and estriol can reduce the intracellular accumulation of imatinib mesylate, and promote the transport ability of P-gp-mediated imatinib mesylate.