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Gentamicin is an aminoglycoside antibiotic which accumulates by endocytosis in the lysosomes of the proximal tubular cells of the kidney and induces apoptosis (El Mouedden et al. 2000, Antimicrob. Chemother Agents; 44:6665-675). This process, depending on the gentamicin concentration, was reproduced on renal cells like LL-C PK1 (El Mouedden et al. 2000, Toxicol. Sci. 56:229-239).
Inside lysosomes, iron could form with gentamicin a complex able to oxydise the lipids or to take part involved in the formation of free radicals. These processes could be responsible for the permeabilisation of the lysosomal membrane, an event susceptible to activate mitochondria and pro-caspase 3 (Servais et al submitted).
The objective of this work was to determine if deferoxamine, a chelator of iron which accumulates preferentially in the lysosomes, could decrease the cellular toxicity induced by gentalin on LLC-PK1 cells as well as the number of cells in apoptosis
These two parameters have been investigated by following the release of lactase deshydrogenase and by counting the number of apoptotic cells after coloration with the DAPI, a known fluorescent marker which intercales in the DNA.
The results indicate a partial protective effect of the deferoxamine when cells are preincubated for 1h or 3h with deferoxamine 25μM and when the iron chelator is maintained for all the duration of incubation with gentamicin (2mM). This partial protective effect probably does not result from a modification of the accumulation of gentamicin. The conditions of use of the deferoxamine must however be strictly controlled due to its own cytotoxic and apoptotic effect.
The mechanisms involved in the protective effect of the deferoxamine apoptosis induced by gentamicin have to be further explored. The deferoxamine would prevent the destabilization of the lysosomial membrane following the formation of the gentamicin/iron-complex or the direct generation of oxygenated radicals, then preventing the release within the cytosol of lysosomal proteases and/or gentamicin, that would then activate mitochondria and the cascade of caspases

Gentamicins --- Deferoxamine --- Aminoglycosides --- Apoptosis