Inhibition of iodoacetamide and t-butylhydroperoxide toxicity in LLC-PK1 cells by antioxidants: a role for lipid peroxidation in alkylation induced cytotoxicity.
Inhibition of iodoacetamide and t-butylhydroperoxide toxicity in LLC-PK1 cells by antioxidants: a role for lipid peroxidation in alkylation induced cytotoxicity.
复制标题
抗氧化剂抑制 LLC-PK1 细胞中碘乙酰胺和叔丁基氢过氧化物的毒性：脂质过氧化在烷基化诱导的细胞毒性中的作用。
DOI：
10.1016/0003-9861(91)90318-d
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发表时间：
1991
影响因子：
3.9
通讯作者：
Stevens,JL
中科院分区：
文献类型：
--
作者：
Chen,Q;Stevens,JL
此前我们曾报道，肾毒性半胱氨酸S偶联物的细胞毒性与硫醇耗竭和脂质过氧化有关，半胱氨酸偶联物是一组毒素，在代谢活化和共价结合后杀死肾癌细胞。为了确定这是否是这些细胞毒性的一般机制，我们比较了抗氧化剂、铁络合剂和硫醇还原剂对烷基化试剂碘乙酰胺(IDAM)和有机过氧剂叔丁基氢过氧化氢(TBHP)的毒性的影响。IBAM或TBHP的毒性与浓度(0.01~1.0 mM)和时间(1~6h)有关。这两种毒素都能引起脂质过氧化，通过乳酸脱氢酶(LDH)的泄漏来确定细胞死亡之前发生的过氧化。IDAM和TBHP的毒性可被抗氧化剂DPPD、BHA、BHQ、PGA、BHT和铁络合剂去铁胺抑制。然而，DPPD可阻断TBHP和IDAM诱导的脂质过氧化和毒性，而不影响细胞内非蛋白硫醇的结合和耗竭。此外，硫醇还原剂二硫苏糖醇还具有抑制脂质过氧化和毒性的作用。因此，在烷化剂作用下，细胞内非蛋白硫醇的耗竭可能与共价结合协同作用，从而导致脂质过氧化和细胞死亡。在LLC-PK1细胞中，烷化剂和有机过氧化物质的毒性似乎有共同的元素。
Previously we reported that thiol depletion and lipid peroxidation were associated with the cytotoxicity of nephrotoxic cysteine S-conjugates, a group of toxins which kill LLC-PK1 cells after metabolic activation and covalent binding. To determine if this is a general mechanism of cytotoxicity in these cells, we compared the effect of antioxidants, an iron chelator, and a thiol reducing agent on the toxicity of an alkylating agent, iodoacetamide (IDAM), and an organic peroxidant,t-butylhydroperoxide (TBHP). IDAM or TBHP toxicity was concentration (0.01 to 1.0 mm) and time (1 to 6 h) dependent. Both toxins caused lipid peroxidation which occurred prior to cell death as determined by leakage of lactate dehydrogenase (LDH). The alkylating agent IDAM bound to cellular macromolecules and depleted cellular nonprotein thiols almost completely by 1 h, while LDH release occurred first at 2 to 3 h. The toxicity of IDAM and TBHP was inhibited by the antioxidants DPPD, BHA, BHQ, PGA, and BHT and the iron chelator deferoxamine. However, DPPD blocked TBHP- and IDAM-induced lipid peroxidation and toxicity without affecting binding and depletion of cellular nonprotein thiols. Furthermore, the thiol reducing agent dithiothreitol was able to block lipid peroxidation and toxicity. Therefore it is possible that with an alkylating agent, depletion of cellular nonprotein thiols cooperates with covalent binding and contributes to lipid peroxidation and cell death. There appear to be common elements in the toxicity of alkylating agents and organic peroxidants in LLC-PK1 cells.