Rybak L P, Ravi R, Somani S M
Department of Pharmacology, Southern Illinois University, School of Medicine, Springfield 62794-9230, USA.
Fundam Appl Toxicol. 1995 Jul;26(2):293-300. doi: 10.1006/faat.1995.1100.
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.
本研究旨在解释二乙基二硫代氨基甲酸盐（DDTC）对顺铂耳毒性的可能保护机制。雄性Wistar大鼠（250 - 275克）接受预处理听觉脑干诱发电位（ABR）检测。不同组大鼠按以下方式注射：（1）顺铂（16毫克/千克腹腔注射），（2）顺铂加DDTC（16毫克/千克腹腔注射 + 600毫克/千克皮下注射），以及（3）对照大鼠。3天后进行治疗后ABR检测，然后对大鼠实施安乐死并采集耳蜗。通过高效液相色谱法分析耳蜗中的谷胱甘肽（GSH）和氧化型谷胱甘肽，并通过分光光度法分析抗氧化酶活性和丙二醛水平。注射顺铂的大鼠在使用短声刺激时，阈值比预处理阈值升高了36±3.05分贝。先注射顺铂然后注射DDTC的大鼠未表现出明显的听力阈值升高。与单独给予顺铂后耳蜗中0.45±0.02纳摩尔/毫克组织相比，DDTC介导的保护作用与更高水平的GSH（0.81±0.11纳摩尔/毫克组织）相关。给予顺铂 + DDTC可使耳蜗谷胱甘肽过氧化物酶（GSH-Px）活性恢复至对照水平。发现顺铂处理的大鼠GSH-Px活性降低（为对照的75%）。与单独注射顺铂的大鼠相比，注射顺铂 + DDTC的动物耳蜗超氧化物歧化酶（SOD）和过氧化氢酶（CAT）活性以及丙二醛水平呈下降趋势。这些数据表明，DDTC对顺铂耳毒性的保护作用与耳蜗GSH/GSH-Px的保留有关。
