| Project/Area Number |
09671738
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Otorhinolaryngology
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| Research Institution | Fukui Medical University |
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Principal Investigator |
SAITO Takehisa Fukui Medical University, Dept. of Otolaryngology, Associate Professor, 医学部, 助教授 (10139769)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAMOTO Takehito Fukui Medical University, Dept. of Otolaryngology, Assistant, 医学部附属病院, 助手 (80303379)
SHIBAMORI Yoshiyuki Fukui Medical University, Dept. of Otolaryngology, Assistant, 医学部附属病院, 助手 (10303380)
NODA Ichiro Fukui Medical University, Dept. of Otolaryngology, Assistant (60283181)
TSUZUKI Hideaki Fukui Medical University, Dept. of Otolaryngology, Assistant (90236927)
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| Project Period (FY) |
1997 – 1998
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| Project Status |
Completed (Fiscal Year 1998)
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| Budget Amount *help |
¥2,700,000 (Direct Cost: ¥2,700,000)
Fiscal Year 1998: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1997: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Keywords | p-glycoprotein / mdrla1a (- / -) mice / blood-inner ear barrier / RT-PCR / immunohistochemistry / auditory brainstem response / pharmacokinetics / neurotoxic agents / 内耳 / 耳毒性 / 血圧・内耳関門 / 血液・脳関門 |
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| Research Abstract |
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
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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
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