title: Cisplatin-induced nephrotoxicity in vitro: increases in cytosolic calcium concentration and the inhibition of cytosolic and mitochondrial protein kinase C.
abstract: 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.
authors.affiliation: Department of Pharmacology and Therapeutics, University of Liverpool, UK.
authors.forename: J G
authors.initials: JG
authors.lastname: Zhang
authors.forename: W E
authors.initials: WE
authors.lastname: Lindup
mesh_terms: 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
chemical_list: 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