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Experimental study on blood-inner ear barrier function in MRP1 and p-glycoprotein gene knockout mice

MRP1和p-糖蛋白基因敲除小鼠血-内耳屏障功能的实验研究

基本信息

批准号：
13671776
负责人：
SAITO Takehisa
金额：
$ 2.3万
依托单位：
Fukui Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671776/
关键词：
p-glycoprotein MRP1 mdr1a gene knockout mouse blood-inner ear barrier RT-PCR immunohistochemistry pharmacokinetics neurotoxic drugs mdr 1a遺伝子欠損マウス

项目摘要

The present study investigated the p-glycoprotein (p-gp) function in the inner ear using mdr1a p-gp gene knock-out mice [mdr1a(-/-) mice] and wild-type mdr1a(+/+) mice. Pharmacokinetic analyses indicated that mdr1a(-/-) mice displayed hypersensitivity to p-gp transported drugs such as doxorubicin (adriamycin) and vinblastine, and increased accumulation of these drugs in the inner ear compared with that in mdr1a(+/+) 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 elevated thresholds and prolongations of wave I and wave I to V interpeak latencies only in mdr1a(-/-) mice after administering with doxorubicin or vinblastine alone. Furthermore, inhibition of p-gp function by co-administration with cyclosporin A in mdr1a(+/+) mice resulted in increased accumulation of doxorubicin and vinblastine in the inner … More ear. After pretreatment with cyclosporin A, hearing impairment was detected in mdr1a(+/+) mice treated with doxorubicin or vinblastine alone. From these results, it was suggested that mdr1a p-gp, which acts as an efflux pump, prevented ototoxicity induced by p-gp substrate drugs such as doxorubicin and vinblastine in wild-type mice.Expression of multidrug resistance protein 1 (MRP1) was detected in the rat cochlea and in the vestibular labyrinth and endolymphatic sac of the guinea pig by immunohistochemical analyses. MRP1 was detected in the lateral wall of the stria vascularis, spiral ligament, spiral prominence and in the cochlear nerve fibers of the modiolus. Furthermore, MRP1 was found in the epithelial lining of the crista ampullaris, utricle, saccule, and epithelial cells of the endolymphatic sac. Since p-gp and MRP1 act as extrusion pumps, they may participate in a bipolar permeation barrier for selected drugs crossing the blood-inner ear barrier resulting in a low concentration of toxic substances and therapeutic drugs in the cochlea, vestibular organs and endolymphatic sac and play an important role in the blood-inner ear barrier. Less

本研究利用mdr1a p-gp基因敲除小鼠[mdr1a(-/-)小鼠]和野生型mdr1a(+/+)小鼠，研究了p-糖蛋白(p-gp)在内耳中的功能。药代动力学分析表明，mdr1a(-/-)小鼠对阿霉素和长春花碱等p-gp转运药物表现出超敏反应，与mdr1a(+/+)小鼠相比，这些药物在内耳的蓄积增加。但给予耳毒性药物顺铂后，p-gp的蓄积量并未增加，说明p-gp对药物的挤压具有选择性。使用听觉脑干反应的电生理学研究表明，仅在mdr1a(-/-)小鼠中，单独给予阿霉素或长春花碱后，阈值升高，I波和I波至V波的峰间潜伏期延长。此外，在mdr1a(+/+)小鼠中，与环孢菌素A共同给药抑制p-gp功能会导致阿霉素和长春花碱在内侧…中蓄积增加。更多的耳朵。在环孢素A预处理后，仅用阿霉素或长春花碱处理的mdr1a(+/+)小鼠出现听力障碍。这些结果表明，mdr1a p-gp作为一种外排泵，可以预防p-gp底物药物如阿霉素和长春新碱对野生型小鼠的耳毒性作用。免疫组织化学方法检测到多药耐药蛋白1(MRP1)在大鼠耳蜗组织以及豚鼠的前庭迷路和内淋巴囊中表达。MRP1表达于蜗牛耳蜗神经纤维、螺旋韧带、血管纹外侧壁和螺旋突部。此外，MRP1还存在于壶腹嵴、椭圆囊、球囊和内淋巴囊的上皮细胞内。由于P-gp和MRP1作为挤出泵，它们可能参与了所选药物通过血-内耳屏障的双极渗透屏障，导致毒性物质和治疗药物在耳蜗器、前庭器官和内淋巴囊中浓度较低，并在血-内耳屏障中发挥重要作用。较少