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外毛细胞Ca^<2+>通道的阻断作用，这种作用可能抑制声音感知系统的第一步。然而，尚不清楚这种作用是否会导致慢性耳毒性或细胞死亡。在本研究中，顺铂的transisomer，即transplatin，被用于体内和体外实验。结果，通过常规膜片钳技术，移植阻断豚鼠离体外毛细胞Ca^<2+>通道的程度几乎与顺铂相同。然而，移植在体内没有肾毒性和耳毒性。从这些结果来看，顺铂可能损害耳蜗感觉生理，但这种作用可能不会发展为慢性耳毒性或细胞死亡。在慢性耳毒性方面，研究了顺铂代谢物对离体外毛细胞的毒性。分离的豚鼠外毛细胞与含顺铂的肝酶组分（S9）孵育。在该溶液中孵育后，外毛细胞的活力明显降低。提示药物代谢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.