Autoxidation of extracellular hydroquinones is a causative event for the cytotoxicity of menadione and DMNQ in A549-S cells.
Autoxidation of extracellular hydroquinones is a causative event for the cytotoxicity of menadione and DMNQ in A549-S cells.
复制标题
细胞外对苯二酚的自氧化是 A549-S 细胞中甲萘醌和 DMNQ 细胞毒性的致病事件。
DOI：
10.1016/s0003-9861(02)00716-6
复制
发表时间：
2003
影响因子：
3.9
通讯作者：
Forman,HenryJay
中科院分区：
文献类型：
--
作者：
Watanabe,Nobuo;Forman,HenryJay
1,4-萘醌的细胞毒性归因于单电子还原酶介导的氧化还原循环产生的细胞内活性氧 (ROS) 以及细胞亲核试剂的芳基化。然而，在这里，我们报道了肺上皮 A549 细胞（A549-S 以前称为 A549-G4S（Watanabe 等人，Am. J. Physiol. 283 (2002) L726-736）的亚克隆中，甲萘醌和 2,3-二甲氧基-1,4-萘醌 (DMNQ) 产生 ROS 的机制，因此与范例不同，两种醌产生的 H2O2 在亚微摩尔水平下可以被双香豆素（NAD(P)H 醌氧化还原酶 (NQO1) 的抑制剂）阻止，无论醌浓度如何，外源 SOD 也会在低浓度但不高浓度的醌（尤其是 DMNQ）下抑制 H2O2 的产生。超氧化物驱动的对苯二酚自氧化作用占两种醌产生 H2O2 的一半以上，而在高醌浓度下，特别是对于 DMNQ，比例化驱动的对苯二酚自氧化作用似乎主要发生在细胞外环境中，而不是在细胞质中，因为细胞外过氧化氢酶可以在整个醌范围内显着减弱醌诱导的细胞毒性。浓度，而内源性过氧化氢酶的完全失活或细胞内谷胱甘肽的完全耗尽对其细胞毒性仅具有边际影响。最后，我们证明ROS的产生是NQO1针对醌芳基化的补偿性防御作用的结果。
Cytotoxicity of 1,4-naphthoquinones has been attributed to intracellular reactive oxygen species (ROS) generation through one-electron-reductase-mediated redox cycling and to arylation of cellular nucleophiles. Here, however, we report that in a subclone of lung epithelial A549 cells (A549-S previously called A549-G4S (Watanabe, et al., Am. J. Physiol. 283 (2002) L726–736), the mechanism of ROS generation by menadione and by 2,3-dimethoxy-1,4-naphthoquinone (DMNQ), and therefore that of cytotoxicity, differs from the paradigm. Ninety percent of H2O2generation by both the quinones can be prevented by dicumarol, an inhibitor of NAD(P)H quinone oxidoreductase (NQO1), at the submicromolar level, regardless of the quinone concentrations. Exogenous SOD also inhibits H2O2production at low but not high concentrations of the quinones, especially DMNQ. Thus, at low quinone concentrations, superoxide-driven hydroquinone autoxidation accounts for more than half of H2O2generation by both quinones, whereas at high quinone concentrations, especially for DMNQ, comproportionation-driven hydroquinone autoxidation becomes the predominant mechanism. Hydroquinone autoxidation appears to occur predominantly in the extracellular environment than in the cytosol as extracellular catalase can dramatically attenuate quinone-induced cytotoxicity throughout the range of quinone concentrations, whereas complete inactivation of endogenous catalase or complete depletion of intracellular glutathione has only a marginal effect on their cytotoxicity. Finally, we show evidence that ROS production is a consequence of the compensatory defensive role of NQO1 against quinone arylation.