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

本研究使用 mdr1a p-gp 基因敲除小鼠 [mdr1a(-/-) 小鼠] 和野生型 mdr1a(+/+) 小鼠研究了内耳中的 p-糖蛋白 (p-gp) 功能。分析表明，mdr1a(-/-) 小鼠对 p-gp 转运药物（如多柔比星（阿霉素）和长春花碱）表现出过敏，并且积累增加与 mdr1a(+/+) 小鼠相比，这些药物在内耳中的积累量并未增加，这表明 p-gp 对使用听觉脑干进行的药物排出研究具有选择性。仅在 mdr1a(-/-) 小鼠给予多柔比星或此外，在 mdr1a(+/+) 小鼠中，与环孢菌素 A 共同给药抑制 p-gp 功能，导致内耳中多柔比星和长春花碱的积累增加。在单独使用阿霉素或长春花碱治疗的 mdr1a(+/+) 小鼠中检测到。 mdr1a p-gp 充当外排泵，可防止野生型小鼠中由 p-gp 底物药物（如多柔比星和长春碱）引起的耳毒性。在大鼠耳蜗和耳蜗中检测到多药耐药蛋白 1 (MRP1) 的表达通过免疫组织化学分析在豚鼠的前庭迷路和内淋巴囊的侧壁中检测到MRP1。此外，在壶腹嵴、椭圆囊、囊和内淋巴囊的上皮细胞中也发现了 MRP1。作为挤出泵，它们可以参与选定药物穿过血液内部的双极渗透屏障耳屏障导致有毒物质和治疗药物在耳蜗、前庭器官和内淋巴囊中的浓度较低，而内耳屏障的血液发挥着重要作用。