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      Cisplatin-induced nephrotoxicity in porcine proximal tubular cells: mitochondrial dysfunction by inhibition of complexes I to IV of the respiratory chain.

      The Journal of pharmacology and experimental therapeutics
      Adenosine Triphosphate, metabolism, Animals, Antineoplastic Agents, toxicity, Carmustine, pharmacology, Cell Survival, drug effects, Cisplatin, Deferoxamine, Electron Transport Complex II, Electron Transport Complex III, antagonists & inhibitors, Electron Transport Complex IV, Glutathione, Glutathione Reductase, Kidney Tubules, Proximal, pathology, Kinetics, Mitochondria, Multienzyme Complexes, NAD(P)H Dehydrogenase (Quinone), Oxidoreductases, Oxygen Consumption, Phenylenediamines, Reactive Oxygen Species, Rotenone, Succinate Dehydrogenase, Swine

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          Cisplatin-induced nephrotoxicity was studied in porcine proximal tubular cells, focusing on the relationship between mitochondrial damage, reactive oxygen species (ROS) and cell death. Cisplatin specifically affected mitochondrial functions: complexes I to IV of the respiratory chain were inhibited 15 to 55% after 20 min of incubation with 50 to 500 microM, respectively. As a result, intracellular ATP was decreased to 70%. The mitochondrial glutathione (reduced form) (GSH)-regenerating enzyme GSH-reductase (GSH-Rd) activity was reduced by 20%, which contributed to a 70% reduction of GSH levels and ROS formation. The residual electron flow through the mitochondrial respiratory chain was the source of ROS because additional inhibition of the complexes I to IV reduced ROS formation. Because cisplatin affects both GSH-Rd and complexes I to IV, cells were incubated with N,N'-bis(2-chloroethyl)-N-nitrosourea (inhibitor of GSH-Rd) and inhibitors of the different complexes. Only N,N'-bis(2-chloroethyl)-N-nitrosourea with rotenone (complex I inhibitor) induced ROS formation, which indicates that inhibition of complex I and inhibition of the GSH-Rd is probably the cause of ROS formation. However, the resulting ROS is not the cause of cell death because diphenyl-p-phenylene-diamine and deferoxamine, which completely prevented ROS, could not prevent cell death. Similarly, the antioxidants did not completely prevent the decrease in activity of complexes I to IV, ATP or GSH levels. In conclusion, ROS formation does occur during cisplatin-induced toxicity, but it is not the direct cause of cell death.

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