COMPARATIVE-STUDIES ON THE MECHANISMS OF PARAQUAT AND 1-METHYL-4-PHENYLPYRIDINE (MPP+) CYTOTOXICITY
COMPARATIVE-STUDIES ON THE MECHANISMS OF PARAQUAT AND 1-METHYL-4-PHENYLPYRIDINE (MPP+) CYTOTOXICITY
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DOI：
10.1016/0006-291x(86)91210-6
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发表时间：
1986-05-29
影响因子：
3.1
通讯作者：
SMITH, MT
中科院分区：
文献类型：
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作者：
DIMONTE, D;SANDY, MS;SMITH, MT
1-甲基-4-苯基吡啶(MPP+)是1-甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP)的有毒代谢物，其结构与除草剂百草枯(PQ++)相似。因此，我们比较了MPP+和PQ++在一个具有良好特征的实验模型上的作用，即分离的大鼠肝细胞。PQ++通过氧化还原循环在细胞内产生活性氧物种，谷胱甘肽还原酶抑制剂1，3-二(2-氯乙基)-1-亚硝脲(BCNU)可增强其对肝细胞的毒性。在BCNU处理的细胞中，PQ++导致GSH耗竭、脂质过氧化和细胞死亡。抗氧化剂N，N‘-二苯基-对苯二胺(DPPD)和铁络合剂去铁胺可阻止这些细胞毒性作用。MPP+也可引起BCNU处理的肝细胞GSH耗竭，但BCNU对MPP+的细胞毒性无明显影响，也不伴有明显的脂质过氧化反应。DPPD和去铁胺也不能阻止MPP+诱导的细胞死亡。我们的结论是，活性氧物种的产生可能在PQ++细胞毒性中起主要作用，而MPP+诱导的细胞损伤可能涉及其他更重要的毒性机制。
1-methyl-4-phenylpyridine (MPP+) is the putative toxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and is structurally similar to the herbicide paraquat (PQ++). We have therefore compared the effects of MPP+and PQ++on a well characterized experimental model, namely isolated rat hepatocytes. PQ++generates reactive oxygen species within cells by redox cycling and its toxicity to hepatocytes was potentiated by pretreatment with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), an inhibitor of glutathione reductase. In BCNU-treated cells, PQ++caused GSH depletion, lipid peroxidation and cell death. These cytotoxic effects were prevented by the antioxidant N,N′-diphenyl-p-phenylenediamine (DPPD) and the iron-chelating agent desferrioxamine. MPP+also caused GSH depletion in BCNU-treated hepatocytes but its cytotoxicity was not markedly affected by BCNU, nor was it accompanied by significant lipid peroxidation. DPPD and desferrioxamine also failed to prevent MPP+-induced cell death. We conclude that the production of active oxygen species is likely to play a major role in PQ++cytotoxicity, while MPP+-induced cell damage may involve additional, more important toxic mechanisms.