Mechanism of Cisplatin Ototoxicity: Antioxidant System

耳毒性 丙二醛 超氧化物歧化酶 谷胱甘肽过氧化物酶 谷胱甘肽还原酶 耳蜗内电位 药理学 顺铂 肾毒性 化学 谷胱甘肽 抗氧化剂 毒性 内分泌学 内科学 医学 生物化学 化疗 豚鼠
作者
Radhika Ravi,Satu M. Somani,Leonard P. Rybak
出处
期刊:Pharmacology & Toxicology [Wiley]
卷期号:76 (6): 386-394 被引量:320
标识
DOI:10.1111/j.1600-0773.1995.tb00167.x
摘要

Abstract: The dose and duration limiting toxic effects of cisplatin are ototoxicity and nephrotoxicity. While several studies have attempted to shed some light on the causes of nephrotoxicity, the reasons for ototoxicity induced by cisplatin are poorly understood. Therefore, this investigation was undertaken to delineate the potential mechanisms underlying cisplatin ototoxicity. The role of glutathione (GSH), oxidized glutathione (GSSG) and malondialdehyde levels, and antioxidant enzyme activities [superoxide dismutase, catalase, GSH peroxidase, and GSH reductase] were examined in cochlear toxicity following an acute dose of cisplatin. Male Wistar rats were treated with various doses of cisplatin. Pretreatment auditory brain stem evoked responses (ABR) were performed and then post‐treatment ABRs and endocochlear potentials were also performed after three days. Acute cochlear toxicity (ototoxicity) was evidenced as elevated hearing thresholds and prolonged wave I latencies in response to various stimuli (clicks and tone bursts at 2, 8, 16 and 32 kHz) on ABRs. The endocochlear potentials were reduced (50% control) in cisplatin‐treated rats as compared to control animals. The rats were sacrified and cochleae isolated. The GSH, GSSG and malondialdehyde levels, and antioxidant enzyme activities were determined. Cisplatin ototoxicity correlated with a decrease in cochlear GSH [0.45±0.012 nmol/mg] after cisplatin administration compared to 0.95±012 nmol/mg in control cochleae (P<0.05). Superoxide dismutase, catalase activities and malondialehyde levels were significantly increased in the cochleae of cisplatin injected rats. Cochlear GSH‐peroxidase and GSH reductase activity significantly decreased after cisplatin administration. Alterations in the activity of antioxidant enzymes, an increase in malondialdehyde levels, and depletion of cochlear GSH suggest a role for reactive oxygen species mediated damage of the cochlea in cisplatin toxicity. These biochemical changes were accompanied by the elevation of ABR threshold that appears to correlate well with alterations in antioxidant systems which could be the cause of cisplatin ototoxicity.
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