Kim Y K, Jung J S, Lee S H, Kim Y W
College of Medicine, Pusan National University, Pusan, 602-739, Korea.
Toxicol Appl Pharmacol. 1997 Oct;146(2):261-9. doi: 10.1006/taap.1997.8252.
Effects of antioxidants, reactive oxygen species (ROS) scavengers, and Ca2+ on cisplatin-induced renal cell injury were studied in rabbit renal cortical slices in vitro. Cisplatin induced LDH release and lipid peroxidation, inhibition of PAH uptake, and GSH depletion. These changes were significantly prevented by thiols (DTT and GSH), antioxidants (DPPD and BHA), and an iron chelator (deferoxamine). Superoxide dismutase partially reduced the cisplatin-induced LDH release without affecting the lipid peroxidation and the GSH depletion. Catalase did not affect the LDH release and the lipid peroxidation induced by cisplatin. Hydroxyl radical scavengers prevented the lipid peroxidation, whereas they did not alter the LDH release, the inhibition of PAH uptake, and the GSH depletion induced by cisplatin. Removal of Ca2+ or addition of EGTA to the incubation medium did not alter cisplatin effects on LDH release and lipid peroxidation. Buffering intracellular Ca2+ with quin-2/AM or inhibition of intracellular Ca2+ release with TMB-8 significantly reduced the cisplatin effect on LDH release without any effect on the lipid peroxidation and the GSH depletion. Ruthenium red attenuated the LDH release, the lipid peroxidation, and the inhibition of PAH uptake mediated by cisplatin. La3+ prevented the cisplatin effect on the LDH release, whereas it did not affect the lipid peroxidation, the inhibition of PAH uptake, and the GSH depletion by cisplatin. These results suggest that cisplatin induces a lethal cell injury by lipid peroxidation-dependent and -independent mechanisms and that the cell injury and the lipid peroxidation by cisplatin are iron-dependent. In addition, the data indicate that the Ca2+ released from intracellular stores, but not the Ca2+ moved from extracellular space, plays a role in the cisplatin-induced cell injury independent of lipid peroxidation.
在体外兔肾皮质切片中研究了抗氧化剂、活性氧（ROS）清除剂和Ca2+对顺铂诱导的肾细胞损伤的影响。顺铂诱导乳酸脱氢酶（LDH）释放和脂质过氧化，抑制对氨基马尿酸（PAH）摄取，并导致谷胱甘肽（GSH）耗竭。硫醇（二硫苏糖醇和GSH）、抗氧化剂（二苯基对苯二胺和丁基羟基茴香醚）和铁螯合剂（去铁胺）可显著预防这些变化。超氧化物歧化酶部分降低了顺铂诱导的LDH释放，但不影响脂质过氧化和GSH耗竭。过氧化氢酶不影响顺铂诱导的LDH释放和脂质过氧化。羟基自由基清除剂可预防脂质过氧化，但不改变顺铂诱导的LDH释放、PAH摄取抑制和GSH耗竭。去除Ca2+或在孵育培养基中添加乙二醇双（2-氨基乙醚）四乙酸（EGTA）不会改变顺铂对LDH释放和脂质过氧化的影响。用喹啉-2/乙酰甲酯（quin-2/AM）缓冲细胞内Ca2+或用8-叔丁基-1,4-二氢-1,4,5,6-四甲基苯并二氮杂䓬-2-硫醇（TMB-8）抑制细胞内Ca2+释放可显著降低顺铂对LDH释放的影响，而对脂质过氧化和GSH耗竭无任何影响。钌红减弱了顺铂介导的LDH释放、脂质过氧化和PAH摄取抑制。镧离子（La3+）可预防顺铂对LDH释放的影响，但不影响顺铂引起的脂质过氧化、PAH摄取抑制和GSH耗竭。这些结果表明，顺铂通过脂质过氧化依赖性和非依赖性机制诱导致命性细胞损伤，且顺铂引起的细胞损伤和脂质过氧化是铁依赖性的。此外，数据表明，从细胞内储存释放的Ca2+，而非从细胞外空间进入的Ca2+，在顺铂诱导的、独立于脂质过氧化的细胞损伤中起作用。
