Gisplatin-mediated impairment of mitochondrial DNA metabolism inversely correlates with glutathione levels
Gisplatin-mediated impairment of mitochondrial DNA metabolism inversely correlates with glutathione levels
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DOI：
10.1042/bj20071615
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发表时间：
2008-08-15
影响因子：
4.1
通讯作者：
Antonio Enriquez, Jose
中科院分区：
文献类型：
--
作者：
Garrido, Nuria;Perez-Martos, Acisclo;Antonio Enriquez, Jose
顺铂在线粒体中积累，线粒体是这种药物在癌细胞中的主要靶点。因此，线粒体功能的改变与癌细胞对化疗剂的抗性有关。此外，顺铂的毒副作用似乎与体内和体外线粒体损伤有关。为了阐明顺铂在空（线粒体DNA）的维持和表达的潜在作用，我们分析了大鼠肝脏mtDNA和mtDNA（线粒体RNA）的合成以及它们在体内治疗对体外暴露于顺铂的影响下的稳定性。我们发现，顺铂导致直接和显着的损害辊和mtDNA的合成，并降低稳定状态水平的mtDNA在分离的线粒体。此外，在体内顺铂治疗的动物发挥了保护作用，从损害的mtDNA代谢引起的体外暴露于药物，通过增加线粒体GSH水平后，体内顺铂治疗。
Cisplatin accumulates in mitochondria, which are a major target for this drug in cancer cells. Thus alterations in mitochondrial function have been implicated in cancer cell resistance to chemotherapeutic agents. Moreover, cisplatin toxic side effects seem to be associated with mitochondrial injury in vivo and in vitro. In order to clarify the potential effect of cisplatin in null (mitochondrial DNA) maintenance and expression, we have analysed rat liver mtDNA and mtRNA (mitochondrial RNA) synthesis as well as their stability under the influence of in vivo treatment on in vitro exposure to cisplatin. We show that cisplatin causes a direct and significant impairment of roll and mtRNA synthesis and decreases steady-state levels of mtRNAs in isolated mitochondria. Furthermore, in vivo treatment of the animals with cisplatin exerts a protective effect from the impairment of mtRNA metabolism caused by in vitro exposure to the drug, by means of increased mitochondrial GSH levels after in vivo cisplatin treatment.