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

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钙通道的阻断作用，这一作用可能抑制声音知觉系统的第一步。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，用传统的膜片钳技术，转铂阻断豚鼠分离的外毛细胞的钙通道的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。

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.