Inhibition of doxorubicin-initiated membrane damage by N-acetylcysteine: possible mediation by a thiol-dependent, cytosolic inhibitor of lipid peroxidation.
Inhibition of doxorubicin-initiated membrane damage by N-acetylcysteine: possible mediation by a thiol-dependent, cytosolic inhibitor of lipid peroxidation.
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N-乙酰半胱氨酸抑制阿霉素引发的膜损伤：可能由硫醇依赖性脂质过氧化胞质抑制剂介导。
DOI：
10.1016/0041-008x(88)90078-6
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发表时间：
1988
影响因子：
3.8
通讯作者：
McCay,PB
中科院分区：
文献类型：
--
作者：
Powell,SR;McCay,PB
过氧化损伤被认为是多柔比星诱导的心脏毒性的一个组成部分。据报道，某些硫醇如N-乙酰半胱氨酸的给药可防止与长期多柔比星给药相关的心脏毒性和死亡率。我们已经研究了N-乙酰半胱氨酸通过抑制多柔比星诱导的脂质过氧化反应来发挥其保护作用的可能性，该过程是由热不稳定的胞质因子介导的。透析的大鼠肝细胞溶质加N-乙酰半胱氨酸显着抑制阿霉素诱导的脂质过氧化反应的微粒体系统，而无论是细胞溶质，也没有N-乙酰半胱氨酸单独这样做。同时，观察到N-乙酰半胱氨酸在含有细胞溶质、微粒体和多柔比星的系统中快速消耗。细胞质对脂质过氧化的抑制以及伴随的N-乙酰半胱氨酸氧化是热不稳定的。大鼠心脏胞质溶胶表现出类似的N-乙酰半胱氨酸依赖性抑制阿霉素诱导的脂质过氧化反应，但心脏胞质溶胶的蛋白质含量的基础上，不如肝胞质溶胶的有效性。心脏胞质溶胶的抗氧化特性以及其氧化N-乙酰半胱氨酸的能力被抑制由碘乙酸的胞质溶胶的预先处理。这表明该因子具有必需的巯基。这些结果表明，肝脏和心脏的细胞质中含有热不稳定的成分，能够利用N-乙酰半胱氨酸作为底物，以抑制阿霉素诱导的微粒体过氧化损伤阿霉素诱导。这些成分可能在N-乙酰半胱氨酸对阿霉素诱导的心脏毒性和死亡率的保护作用中发挥作用。
Peroxidative damages are thought to be a component of doxorubicin-induced cardiac toxicity. Administration of certain thiols, such as N-acetylcysteine, are reported to be protective against the cardiac toxicity and mortality associated with chronic doxorubicin administration. We have investigated the possibility that N-acetylcysteine exerts its protective effect by inhibiting doxorubicin-induced lipid peroxidation in a process mediated by a heat-labile cytosolic factor. Dialyzed rat liver cytosol plus N-acetylcysteine significantly inhibited doxorubicin-induced lipid peroxidation in a microsomal system whereas neither cytosol nor N-acetylcysteine alone does so. Concomitantly, it was observed that N-acetylcysteine is rapidly consumed in a system containing cytosol, microsomes, and doxorubicin. The inhibition of lipid peroxidation by the cytosol and accompanying N-acetylcysteine oxidation is heat labile. Rat heart cytosol showed a similar N-acetylcysteine-dependent inhibition of doxorubicin-induced lipid peroxidation, but heart cytosol was less potent than hepatic cytosol on the basis of protein content. The antioxidant property of heart cytosol as well as its capacity to oxidize N-acetylcysteine was inhibited by prior treatment of the cytosol with iodoacetic acid. This suggested that the factor possessed essential sulfhydryl groups. These results suggest that hepatic and cardiac cytosols contain heat-labile components capable of utilizing N-acetylcysteine as a substrate to suppress the doxorubicin-induced peroxidative damage to microsomes induced by doxorubicin. These components may play a role in the protective effects of N-acetylcysteine against doxorubicin-induced cardiac toxicity and mortality.
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