Zhang J G, Lindup W E
Department of Pharmacology and Therapeutics, University of Liverpool, U.K.
Pharmacol Toxicol. 1996 Oct;79(4):191-8. doi: 10.1111/j.1600-0773.1996.tb02087.x.
Cisplatin-induced cytotoxicity has been investigated with rat renal cortical slices in vitro. Incubation of renal slices with cisplatin caused an unexpected decrease in NADH-dependent. lucigenin-enhanced chemiluminescence in the homogenate of the slices in a time- and concentration-dependent fashion. Cisplatin caused a concentration-related (0.2 1 mM) decrease in the formation of NADH-dependent superoxide anion. Cisplatin (2 mM) significantly suppressed the chemiluminescence to 70% of control as early as 15 min, and to 15% after 90 min. of incubation. A decrease was also observed 90 min. after incubation of slices with 0.25 mM cisplatin. In addition, the activities of superoxide dismutase (SOD) and catalase in the slices were significantly increased after 60 min. of exposure to cisplatin (2 mM) while decreases in the activities of glutathione (GSH) peroxidase and GSSG reductase became significant at 90 and 120 min. of incubation respectively. SOD and catalase activities were increased by 1.6 and 1.5 fold respectively after 90 min. of incubation and the activities of GSH peroxidase and GSSG reductase were decreased to 82% and 72% of control, respectively at 120 min. Both dithiothreitol (2 mM), a sulphydryl agent and diphenylphenylenediamine (5 microM), an antioxidant, protected against cisplatin-induced leakage of lactate dehydrogenase, lipid peroxidation and decreases of GSH peroxidase and GSSG reductase but had no effect on the decrease of chemiluminescence caused by cisplatin. The results suggest that neither an increase in the production of NADH-dependent superoxide anion nor a decrease in activity of several antioxidant enzymes were directly responsible for cisplatin-induced lipid peroxidation.
已在体外使用大鼠肾皮质切片研究了顺铂诱导的细胞毒性。用顺铂孵育肾切片会导致切片匀浆中烟酰胺腺嘌呤二核苷酸（NADH）依赖性、光泽精增强的化学发光以时间和浓度依赖性方式意外降低。顺铂导致NADH依赖性超氧阴离子形成呈浓度相关（0.2 - 1 mM）降低。顺铂（2 mM）早在孵育15分钟时就将化学发光显著抑制至对照的70%，孵育90分钟后降至15%。在用0.25 mM顺铂孵育切片90分钟后也观察到了降低。此外，在暴露于顺铂（2 mM）60分钟后，切片中超氧化物歧化酶（SOD）和过氧化氢酶的活性显著增加，而谷胱甘肽（GSH）过氧化物酶和谷胱甘肽二硫化物（GSSG）还原酶的活性分别在孵育90分钟和120分钟时显著降低。孵育90分钟后，SOD和过氧化氢酶的活性分别增加了1.6倍和1.5倍，在120分钟时，GSH过氧化物酶和GSSG还原酶的活性分别降至对照的82%和72%。巯基试剂二硫苏糖醇（2 mM）和抗氧化剂二苯基苯二胺（5 microM）均能保护细胞免受顺铂诱导的乳酸脱氢酶泄漏、脂质过氧化以及GSH过氧化物酶和GSSG还原酶活性降低的影响，但对顺铂引起的化学发光降低没有作用。结果表明，NADH依赖性超氧阴离子产生的增加或几种抗氧化酶活性的降低都不是顺铂诱导脂质过氧化的直接原因。
