CISPLATIN INDUCES N-ACETYL CYSTEINE SUPPRESSIBLE F-2-ISOPROSTANE PRODUCTION AND INJURY IN RENAL TUBULAR EPITHELIAL-CELLS

In the low intracellular chloride milieu, chloride ions of cisplatin m ay exchange for cellular SH moieties resulting in glutathione depletio n, H2O2 accumulation, and lipid peroxidation, Cisplatin-induced lipid peroxidation, in addition to causing direct cellular injury, may furth er contribute to cisplatin-induced renal dysfunction by generating vas oconstrictive E-2- and F-2-isoprostanes. The aim of this study was to determine whether cisplatin-induced renal epithelial (LLC-PK1 and prim ary human proximal tubular) cell injury is associated with increased p roduction of isoprostanes, and whether this can be suppressed with a t hiol donor, N-acetyl cysteine. It was confirmed that incubation of ren al epithelial cells with cisplatin resulted in N-acetyl cysteine-inhib itable glutathione depletion, H2O2 accumulation, Lipid degradation, an d lactate dehydrogenase release. In additional experiments, incubation of cells with cisplatin for 48 h was accompanied by a dose-related in crease in total (free plus esterified) F-2-isoprostanes. An increase i n F-2-isoprostanes was discernible at 16.5 mu M cisplatin and doubled at 66.0 mu M. N-Acetyl cysteine at 50 mu M concentration effectively s uppressed 66.0 mu M cisplatin-induced increase in isoprostanes. Simila r findings were also obtained in human cells. Thus, cisplatin-induced tubular cell injury is accompanied by increased isoprostane production through a mechanism involving thiol depletion. On the basis of this n ew finding, it is hypothesized that these arachidonic acid peroxidatio n products may be partially responsible for the cisplatin-induced rena l vasoconstriction demonstrable in the in vivo models.