ELECTROPHYSIOLOGICAL AND BIOCHEMICAL STUDY ON ACUTE AND CHRONIC OTOTOXIC MECHANISMS BY CISPLATIN

顺铂急性和慢性耳毒性机制的电生理和生化研究

• 批准号: 05671421
• 负责人: SAITO Takehisa
• 金额: $ 1.28万
• 依托单位: FUKUI MEDICAL SCHOOL
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1994
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05671421/
• 关键词: CISPLATIN; TRANSPLATIN; OTOTOXIC MECHANISM; OUTER HAIR CELLS; CALCIUM CHANNEL; METABOLITE; 電位依存性Ca^<2+>チャンネル; 代謝酵素; 単離外有毛細胞

It has been proposed by our recent studies that a part of the acute ototoxic mechanism involved the blocking action on the Ca^<2+> channel of outer hair cells and this action might suppress the first step of sound perception system. It has not yet been clarified, however, whether this action lead to chronic ototoxicity or cell death.In this study, transisomer of cisplatin, transplatin, has been used in vivo and in vitro experiments. As a result, transplatin blocked the Ca^<2+> channel of isolated outer hair cells of the guinea pig to almost the same degree as cisplatin by using conventional patch-clamp technique. However, transplation had no nephrotoxicity and ototoxicity in vivo. From these results, cisplatin may impair the cochlear sensory physiology, but this action may not progress to chronic ototoxicity or cell death.Concerning the chronic ototoxicity, the toxicity of cisplatin metabolite on isolated outer hair cells was investigated. Isolated outer hair cells of the guinea pig were incubated with hepatic enzymatic fraction (S9) containing cisplatin. The viability of outer hair cells significantly decreased after incubation in this solution. It was suggested that drug metabolites and induction of metabolic enzymes were important facters in chronic ototoxicity.

我们最近的研究提出，急性耳毒性机制的一部分涉及对外毛细胞Ca~(2+)通道的阻断作用，这一作用可能抑制声感觉系统的第一步。然而，这一作用是否会导致慢性耳毒性或细胞死亡尚不清楚。在本研究中，顺铂的传递体，即顺铂，已在体内和体外实验中使用。结果表明，用传统的膜片钳技术，转铂对豚鼠分离的外毛细胞的钙通道的阻断程度几乎与顺铂相同。但体内移植无肾毒性和耳毒性。从这些结果来看，顺铂可能损害耳蜗感觉神经生理，但这一作用可能不会进展到慢性耳毒性或细胞死亡。针对慢性耳毒性，研究了顺铂代谢产物对分离的外毛细胞的毒性。分离的豚鼠外毛细胞与含顺铂的肝酶组分(S9)孵育。外毛细胞在该溶液中孵育后活力显著下降。提示药物代谢产物和代谢酶的诱导是慢性耳毒性的重要因素。

项目成果

斉藤武久: "シスプラチン投与間隔の違いによる蝸牛外有毛細胞毒性の差" Audiology Japan. 37. 719-725 (1994)

Takehisa Saito：“顺铂给药间隔差异导致的耳蜗外毛细胞毒性差异”Audiology Japan 37. 719-725 (1994)。

Saito T.: "Ototoxicity of cisplatin and aminoglycosides on isolated outer hair cells" Pract.Otol. (Kyoto). Suppl.63. 47-52 (1993)

Saito T.：“顺铂和氨基糖苷类药物对分离的外毛细胞的耳毒性”Pract.Otol。

斉藤武久: "単離外有毛細胞からみたシスプラチンとアミノ配糖体耳毒性" 耳鼻臨床. 補63. 47-52 (1993)

Takehisa Saito：“从分离的外毛细胞观察到的顺铂和氨基糖苷类耳毒性”Otorhinolaryngology 63. 47-52 (1993)。

Yamamoto T.: "Cisplatin blocks voltage-dependent calcium current in dissociated outer hair cells of guinea-pig cochlea" Brain Research. 648. 296-298 (1994)

Yamamoto T.：“顺铂阻断豚鼠耳蜗分离的外毛细胞中电压依赖性钙电流”大脑研究。

Saito T.: "X-ray microanalysis and ion microscopy of guinea pig cochlea and kidney after cisplatin treatment" ORL. 56. 310-314 (1994)

Saito T.：“顺铂治疗后豚鼠耳蜗和肾脏的 X 射线微量分析和离子显微镜”ORL。