Cisplatin ototoxicity: Involvement of iron and enhanced formation of superoxide anion radicals

Since there are indications that iron influences cisplatin nephrotoxicity, we studied the role of iron in cisplatin ototoxicity in an in vitro model o f the neurosensory epithelium of the guinea pig cochlea. Viability tests sh owed that Deiters and Hensen cells were not damaged and inner hair cells we re only slightly damaged by cisplatin (50 muM). The outer hair cells were m ost sensitive to cisplatin toxicity. The iron chelator 2,2'-dipyridyl provi ded partial protection against cisplatin-induced cell death. In addition, w e studied the influence of the iron chelators 2,2'-dipyridyl and deferoxami ne on the chelatable iron pool in the various cells of the neurosensory epi thelium using the fluorescent iron indicator Phen Green SK. Both chelators decreased the chelatable iron accessible to Phen Green SK, although the eff ect of deferoxamine was weaker because it entered the cells more slowly. Th e cellular concentration of the chelatable iron was measured using Phen Gre en SK and quantitative laser scanning microscopy. The concentration of chel atable iron in the inner ear cells ranged from 1.3 +/- 0.4 muM iron in inne r hair cells to 3.7 +/- 1.7 muM iron in Hensen cells and did not correlate with the various cell types' susceptibility to cisplatin. Furthermore, cisp latin did not raise the intracellular chelatable iron concentration but enh anced the production of superoxide anions inside the neurosensory epitheliu m, especially inside the hair cells, as detected by the nitrotetrazolium bl ue reduction assay. Our conclusion is that cisplatin ototoxicity is partial ly mediated by an iron-dependent pathway and is associated with an enhanced formation of superoxide anions. (C) 2001 Academic Press.