Role of mitochondria in cisplatin-induced oxidative damage exhibited by rat renal cortical slices.
The role of mitochondria with regard to cisplatin-induced renal toxicity has been examined in vitro. The mitochondria were prepared from rat renal cortical slices which had been exposed to cisplatin. Incubation of the kidney slices with 2 mM cisplatin for various periods depleted glutathione (GSH) and increased thiobarbituric acid reactive substances (TBARS) in a time-dependent manner, a change which indicates lipid peroxidation in the mitochondria. The content of GSH was significantly depleted within 15 min of incubation, while TBARS formation was increased after 60 min of incubation. Marked depletion (30%) of GSH and increased TBARS formation (2-fold) were observed after 60 min and 120 min of incubation, respectively. Furthermore, cisplatin also depleted GSH and induced TBARS formation in the mitochondria in a concentration-dependent fashion. Cisplatin (0.5 mM) depleted GSH, but did not increase the production of TBARS. In addition, the fluorescence intensity of 8-anilino-1-naphthalenesulphonic acid (ANS)-bound to mitochondrial membranes was decreased after 120 min of incubation with 2 mM cisplatin. Several parameters were measured as indicators of damage to mitochondria and cellular integrity and they showed that cytotoxicity occurred subsequent to both GSH depletion and TBARS formation. Cisplatin-induced depletion of GSH is an early event and a determinant step in oxidative stress to mitochondria in the kidney cortex and may lead to irreversible cell injury.
Department of Pharmacology and Therapeutics, University of Liverpool, U.K.
J G
JG
Zhang
W E
WE
Lindup
D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D002945:Cisplatin / Q000633:toxicity*; D005969:Glutamate Dehydrogenase / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D007672:Kidney Cortex / Q000187:drug effects* / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis
D017392:Thiobarbituric Acid Reactive Substances; D005969:Glutamate Dehydrogenase; D001219:Aspartate Aminotransferases; D005978:Glutathione; D002945:Cisplatin