Dose response of carboplatin-induced hearing loss in rats: antioxidant defense system.
Carboplatin, a platinum-containing anticancer drug, is currently being used against a variety of cancers. However, a single high dose of carboplatin is ototoxic in cancer patients. This is the first study to show carboplatin-induced hearing loss in a rat model. Male Wistar rats were divided into five groups and treated as follows: (1) control (saline, intraperitoneally (i.p.)); (2) carboplatin (64 mg/kg, i.p.); (3) carboplatin (128 mg/kg i.p.); (4) carboplatin (192 mg/kg, i.p.) and (5) carboplatin (256 mg/kg, i.p.). Animals in all groups were sedated with ketamine/xylazine and auditory brain-evoked responses (ABRs) were recorded before and 4 days after treatments. The animals were sacrificed on the fourth day and cochleae were harvested and analyzed. Carboplatin dose-dependently decreased body weight. However, at higher doses of carboplatin (192 and 256 mg/kg), there was a significant elevation of hearing threshold shifts at clicks, 4, 8, 16 and 32 kHz tone burst stimuli. The higher doses of carboplatin (192 and 256 mg/kg) significantly increased cochlear lipid peroxidation (132 and 146% of control) and depleted cochlear glutathione levels (66 and 63% of control), respectively. The antioxidant enzyme activities such as superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione-S-transferase (GST) depressed significantly at higher doses of carboplatin. The data suggest that higher doses of carboplatin (above 128 mg/kg) induce hearing loss as evidenced by significant changes in ABRs, lipid peroxidation and antioxidants in the cochlea of rats.
Husain
K
K
Department of Pharmacology, Southern Illinois University School of Medicine, Springfield 62794-9629, USA. khusain@siumed.edu
Scott
R B
RB
Whitworth
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C
Somani
S M
SM
Rybak
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LP
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000633:toxicity*; D000975:Antioxidants / Q000378:metabolism*; D001309:Auditory Threshold / Q000187:drug effects; D016190:Carboplatin / Q000008:administration & dosage* / Q000633:toxicity*; D002374:Catalase / Q000037:antagonists & inhibitors; D003051:Cochlea / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D003638:Deafness / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000633:toxicity; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000037:antagonists & inhibitors; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D000975:Antioxidants; D004791:Enzyme Inhibitors; D008315:Malondialdehyde; D016190:Carboplatin; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D005980:Glutathione Reductase; D005982:Glutathione Transferase; D005978:Glutathione