Cisplatin nephrotoxicity: decreases in mitochondrial protein sulphydryl concentration and calcium uptake by mitochondria from rat renal cortical slices.
The effects of cisplatin on several aspects of the function of mitochondria isolated from the rat renal cortex have been investigated in vitro. Incubation of renal cortical slices with cisplatin (2 mM) caused a rapid loss of mitochondrial protein-SH followed by a substantial decrease in Ca2+ uptake by the mitochondria and a decline in the mitochondrial membrane potential, which was assessed by rhodamine 123 uptake by the slices. Dithiothreitol, a glutathione (GSH)-reducing agent, significantly reversed the alterations in protein-SH, Ca2+ accumulation and rhodamine 123 uptake. There was also a marked amelioration of cisplatin-induced cytotoxicity, as shown by the decreased leakage of several enzymes from the slices. Diethylmaleate, a GSH depletor, enhanced both the cisplatin-induced increase in toxicity, as assessed by enzyme leakage, and also the decreases in protein-SH, Ca2+ accumulation and rhodamine 123 uptake. The antioxidant N,N'-diphenylphenylenediamine substantially alleviated cisplatin toxicity but did not protect against cisplatin-induced alterations to protein-SH and Ca2+ uptake. In addition, the cytotoxicity caused by cisplatin was not affected by cyclosporin A, an inhibitor of Ca2+ release from mitochondria and ruthenium red, an inhibitor of the reuptake of Ca2+. It was concluded that loss of mitochondrial protein-SH and a decrease of Ca2+ uptake are implicated in the toxicity of cisplatin and that mitochondrial GSH is an important factor in relation to oxidative stress to mitochondria and cytotoxicity.
Zhang
J G
JG
Department of Pharmacology and Therapeutics, University of Liverpool, U.K.
Lindup
W E
WE
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002945:Cisplatin / Q000037:antagonists & inhibitors / Q000633:toxicity*; D003470:Culture Media / Q000032:analysis; D005260:Female; D066298:In Vitro Techniques; D007672:Kidney Cortex / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008564:Membrane Potentials; D008928:Mitochondria / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020112:Rhodamine 123; D012235:Rhodamines / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism*
D003470:Culture Media; D012235:Rhodamines; D013438:Sulfhydryl Compounds; D020112:Rhodamine 123; D002945:Cisplatin; D002118:Calcium