Cisplatin-induced nephrotoxicity in vitro: increases in cytosolic calcium concentration and the inhibition of cytosolic and mitochondrial protein kinase C.
Exposure of rat kidney cortical slices to cisplatin (2 mM) significantly increased the activity of cytosolic phosphorylase a, indicating that the concentration of cytosolic Ca2+ was increased. Dithiothreitol (DTT), a sulphydryl reducing agent, markedly reversed this effect but N,N'-diphenylphenylenediamine (DPPD), an antioxidant, did not. Cisplatin inhibited protein kinase C (PKC) activity in both mitochondrial and cytosolic fractions after the slices were exposed to cisplatin. Both DTT and DPPD prevented these inhibitory effects of cisplatin on PKC but diethylmaleate, a glutathione depletor, potentiated this inhibitory effect. These results suggest that the increase in cytosolic Ca2+ is related to depletion of SH-groups, but independent of lipid peroxidation, whereas inhibition of PKC may be associated with cisplatin-induced depletion of thiols and with lipid peroxidation.
Zhang
J G
JG
Department of Pharmacology and Therapeutics, University of Liverpool, UK.
Lindup
W E
WE
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002118:Calcium / Q000032:analysis; D002945:Cisplatin / Q000633:toxicity*; D003600:Cytosol / Q000201:enzymology*; D004229:Dithiothreitol / Q000494:pharmacology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D007672:Kidney Cortex / Q000187:drug effects* / Q000201:enzymology; D008928:Mitochondria / Q000201:enzymology*; D010655:Phenylenediamines / Q000494:pharmacology; D010762:Phosphorylase a / Q000187:drug effects / Q000378:metabolism; D011493:Protein Kinase C / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D010655:Phenylenediamines; C004845:N,N'-diphenyl-4-phenylenediamine; D010762:Phosphorylase a; D011493:Protein Kinase C; D002945:Cisplatin; D002118:Calcium; D004229:Dithiothreitol