In Vitro And In Vivo Evidence Suggesting A Role For Iron In Cisplatin(CP)-induced Nephrotoxicity. † 1638

The therapeutic activity of CP - a widely used antineoplastic agent is limited by serious nephrotoxicity. The underlying mechanism of this nephrotoxicity is still not well known. Although reactive oxygen metabolites(ROM) have been implicated in this model of renal injury, the role of iron which is critical in the generation of other highly toxic free radicals has not been previously examined. We examined the catalytic iron content and the effect of iron chelators in an in vitro model of CP-induced cytotoxicity in LLC-PK1 cells (renal proximal tubular epithelial cells) and an in vivo model of CP-induced acute renal failure in rats. Exposure of LLC-PK1 cells to CP(200 ug/ml, 2.5 hrs) led to a significant increase in bleomycin detectable iron (iron capable of catalyzing free radical reactions) released into the medium (Control: 1.06 ± 0.27, CP: 5.86 ± 0.46 nmol/mg protein, n= 4, p < 0.01). Concurrent incubation of LLC-PK1 cells with iron chelators including deferoxamine and 1.10-phenanthroline significantly attenuated CP-induced cytotoxicity as measured by LDH release.Table

Table 1

The catalytic iron content was significantly increased in the kidney in rats treated with CP (10 mg/kg) and sacrificed 72 hrs later (Control: 0.85± 0.06, CP: 1.7 ± 0.09 nmol/mg protein, n= 5, p < 0.01). DFO provided marked functional (as measured by creatinine and BUN) as well as histological protection against CP-induced acute renal failure.Table

Table 2

*p < 0.01, vs CP alone. Our data strongly support -a critical role of iron in CPinduced nephrotoxicity.