Mechanism of protection by diethyldithiocarbamate against cisplatin ototoxicity: antioxidant system.
This investigation was undertaken to explain the possible, mechanism(s) of protection by diethyldithiocarbamate (DDTC) against cisplatin ototoxicity. Male Wistar rats (250-275 g) underwent pretreatment auditory brain stem-evoked responses (ABRs). The different groups of rats were injected as follows: (1) cisplatin (16 mg/kg i.p.), (2) cisplatin plus DDTC (16 mg/kg i.p. + 600 mg/kg, s.c.), and (3) control rats. Post-treatment ABRs were performed after 3 days and the rats were euthanized and cochleae were harvested. The cochleae were analyzed for glutathione (GSH) and oxidized glutathione, by HPLC, and for the activities of the antioxidant enzymes, and malondialdehyde levels, by spectrophotometry. The cisplatin-injected rats showed a threshold elevation of 36 +/- 3.05 dB above the pretreatment thresholds using click stimulus. Rats treated with cisplatin and then DDTC did not show a significant elevation of hearing threshold. DDTC-mediated protection was associated with higher levels of GSH (0.81 +/- 0.11 nmol/mg tissue), compared to 0.45 +/- 0.02 nmol/mg tissue following administration of cisplatin alone. Administration of cisplatin + DDTC restored the cochlear GSH-Px activity to control level. Cisplatin-treated rats were found to have decreased GSH-Px activity (75% of control). Cochlear SOD and CAT activities and MDA levels showed a decreasing trend in the animals injected with cisplatin + DDTC, compared to cisplatin-alone-treated rats. These data suggest that the protection conferred by DDTC against cisplatin ototoxicity is associated with sparing of the cochlear GSH/GSH-Px.
Rybak
L P
LP
Department of Pharmacology, Southern Illinois University, School of Medicine, Springfield 62794-9230, USA.
Ravi
R
R
Somani
S M
SM
D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D002945:Cisplatin / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D003051:Cochlea / Q000187:drug effects* / Q000201:enzymology; D004050:Ditiocarb / Q000627:therapeutic use*; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects*; D005978:Glutathione / Q000187:drug effects; D005979:Glutathione Peroxidase / Q000187:drug effects; D008297:Male; D051381:Rats; D017208:Rats, Wistar
D000975:Antioxidants; D004050:Ditiocarb; D005979:Glutathione Peroxidase; D005978:Glutathione; D002945:Cisplatin