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 otot oxicity. 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 ip), (2) cisplatin plus D DTC (16 mg/kg ip + 600 mg/kg, sc), and (3) control rats. Post-treatmen t ABRs were performed after 3 days and the rats were euthanized and co chleae were harvested, The cochleae were analyzed for glutathione (GSH ) and oxidized glutathione, by HPLC, and for the activities of the ant ioxidant enzymes, and malondialdehyde levels, by spectrophotometry. Th e cisplatin-injected rats showed a threshold elevation of 36 +/- 3.05 dB above the pretreatment thresholds using click stimulus. Rats treate d with cisplatin and then DDTC did not show a significant elevation of hearing threshold, DDTC-mediated protection was associated with highe r levels of GSH (0.81 +/- 0.11 nmol/mg tissue), compared to 0.45 +/- 0 .02 nmol/mg tissue following administration of cisplatin alone. Admini stration 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 cisplat in + DDTC, compared to cisplatin-alone-treated rats. These data sugges t that the protection conferred by DDTC against cisplatin ototoxicity is associated with sparing of the cochlear GSH/GSH-Px. (C) 1995 Societ y of Toxicology.