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 of the neurosensory epithelium of the guinea pig cochlea. Viability tests showed that Deiters and Hensen cells were not damaged and inner hair cells were only slightly damaged by cisplatin (50 microM). The outer hair cells were most sensitive to cisplatin toxicity. The iron chelator 2,2'-dipyridyl provided partial protection against cisplatin-induced cell death. In addition, we studied the influence of the iron chelators 2,2'-dipyridyl and deferoxamine on the chelatable iron pool in the various cells of the neurosensory epithelium using the fluorescent iron indicator Phen Green SK. Both chelators decreased the chelatable iron accessible to Phen Green SK, although the effect of deferoxamine was weaker because it entered the cells more slowly. The cellular concentration of the chelatable iron was measured using Phen Green SK and quantitative laser scanning microscopy. The concentration of chelatable iron in the inner ear cells ranged from 1.3 +/- 0.4 microM iron in inner hair cells to 3.7 +/- 1.7 microM iron in Hensen cells and did not correlate with the various cell types' susceptibility to cisplatin. Furthermore, cisplatin did not raise the intracellular chelatable iron concentration but enhanced the production of superoxide anions inside the neurosensory epithelium, especially inside the hair cells, as detected by the nitrotetrazolium blue reduction assay. Our conclusion is that cisplatin ototoxicity is partially mediated by an iron-dependent pathway and is associated with an enhanced formation of superoxide anions.
Dehne
N
N
Department of Otorhinolaryngology, University of Essen, Essen, Germany.
Lautermann
J
J
Petrat
F
F
Rauen
U
U
de Groot
H
H
D015082:2,2'-Dipyridyl / Q000494:pharmacology; D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology; D002945:Cisplatin / Q000633:toxicity*; D003051:Cochlea / Q000187:drug effects / Q000294:innervation; D003638:Deafness / Q000139:chemically induced*; D003676:Deferoxamine / Q000494:pharmacology; D004848:Epithelium / Q000187:drug effects; D005260:Female; D005456:Fluorescent Dyes / Q000494:pharmacology; D006168:Guinea Pigs; D006199:Hair Cells, Auditory, Inner / Q000187:drug effects; D018072:Hair Cells, Auditory, Outer / Q000187:drug effects; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D008856:Microscopy, Fluorescence; D009580:Nitroblue Tetrazolium; D009930:Organic Chemicals; D010084:Oxidation-Reduction; D013481:Superoxides / Q000378:metabolism*
D000634:Aminoquinolines; D000970:Antineoplastic Agents; D002614:Chelating Agents; D005456:Fluorescent Dyes; D007502:Iron Chelating Agents; D009930:Organic Chemicals; C431805:Phen Green SK; D013481:Superoxides; D009580:Nitroblue Tetrazolium; D015082:2,2'-Dipyridyl; D007501:Iron; D003676:Deferoxamine; C035739:Quin2; D002945:Cisplatin; D002118:Calcium