Comparison of expression of p-glycoprotein and its function between wild type and mdr 1 a p-glycoprotein gene knock-out mice

近年来的研究表明，mdrla p-糖蛋白（p-gp）定位于脑毛细血管内皮细胞，在血脑屏障中起着重要的外排泵作用，是肿瘤细胞的多药耐药基因。虽然我们以前的报道表明，豚鼠内耳毛细血管内皮细胞也表达p-gp，但其在内耳中的功能仍然不清楚。本研究使用mdrla p-gp基因敲除小鼠[mdrla（-/-）小鼠]和野生型mdrla（+/+）小鼠研究内耳中p-gp的功能。RT-PCR检测野生型小鼠内耳组织中mdrla p-gp编码基因的表达。免疫组化结果显示，在mdrla（+/+）小鼠内耳血-内耳屏障处的毛细血管内皮细胞中有高水平的p-gp表达，而mdrla（-/-）小鼠则无p-gp表达。药代动力学分析表明， ...更多信息 与mdrla（+/+）小鼠相比，t mdrla（-/-）小鼠显示出对p-gp转运药物如阿霉素（阿霉素）和长春碱的超敏反应，并且这些药物在内耳中的蓄积增加（1.22- 7.71倍）。然而，与耳毒性药物顺铂给药后，没有检测到增加的积累，表明p-gp具有选择性挤出药物。应用听性脑干反应的电生理研究表明，给予阿霉素或长春碱后，只有mdrla（-/-）小鼠的I波和I至V波间期的阈值偏移和重叠。此外，在mdrla（+/+）小鼠中，通过与环孢菌素A联合给药抑制P-gp功能导致内耳中阿霉素蓄积增加（2.46倍）和听力损伤。这些结果表明，mdrla p-gp作为外排泵，阻止了p-gp底物药物引起的耳毒性，并在血-内耳屏障中发挥了新的作用机制。少

Recent studies have shown that mdrla p-glycoprotein (p-gp), which conferred multidrug resistance against tumor cells, was located in the brain capillary endothelial cells and played an important role as an extrusion pump in blood-brain barrier. Although it has been shown from our previous report that p-gp was also expressed in the inner ear capillary endothelial cells of the guinea pig, its functional involvement in the inner ear was remained obscure. The present study investigated the p-gp function in the inner ear using mdrla p-gp gene knock-out mice [mdrla(-/-) mice] and wild type mdrla(+/+) mice. Using RT-PCR analysis, mdrla p-gp-encoding gene was detected in the inner ear tissue of the wild type mice. Immunohistochemical study demonstrated that high level expression of p-gp was detected in the capillary endothelial cells of mdrla(+/+) mice inner ear at the site of blood-inner ear barrier, while no p-gp expression was noted in mdrla(-/-) mice. Pharmacokinetic analyses indicated tha … More t mdrla(-/-) mice displayed hypersensitivity to p-gp transported drugs such as doxorubicin (adriamycin) and vinblastine, and increased accumulation of these drugs in the inner ear (1.22-to 7.71-fold) compared with that in mdrla(+/+) mice. However, increased accumulation was not detected after administering with ototoxic drug cisplatin, indicating that p-gp had a selectivity for extruding drugs. Electrophysiological studies using auditory brainstem response showed threshold shifts and prolongations of wave I and wave I to V interpeak latencies only in mdrla(-/-) mice after administering with adriamycin or vinblastine. Furthermore, inhibition of p-gp function by co-administration with cyclosporin A in mdrla(+/+) mice resulted in increased accumulation (2.46-fold) of adriamycin in the inner ear and hearing impairment . From these results, it was suggested that mdrla p-gp, which acts as an efflux pump, prevented ototoxicity induced by p-gp substrate drugs and contributed to a new functional mechanism in the blood-inner ear barrier. Less