Mechanism of cisplatin ototoxicity: antioxidant system.
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 sacrificed 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 malondialdehyde levels were significantly increased in the cochleae of cisplatin injected rats. Cochlear GSH-peroxidase and GSH reductase activity significantly decreased after cisplatin administration.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D002945:Cisplatin / Q000633:toxicity*; D003051:Cochlea / Q000187:drug effects / Q000201:enzymology*; D003055:Cochlear Microphonic Potentials / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects; D005978:Glutathione / Q000187:drug effects; D005979:Glutathione Peroxidase / Q000187:drug effects; D006309:Hearing / Q000187:drug effects* / Q000502:physiology; D051381:Rats
D000975:Antioxidants; D005979:Glutathione Peroxidase; D005978:Glutathione; D002945:Cisplatin