Increased Cytotoxicity of 3-Morpholinosydnonimine to HepG2 Cells in the Presence of Superoxide Dismutase
Increased Cytotoxicity of 3-Morpholinosydnonimine to HepG2 Cells in the Presence of Superoxide Dismutase
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超氧化物歧化酶存在下 3-吗啡啉亚胺对 HepG2 细胞的细胞毒性增加
DOI：
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发表时间：
1995
影响因子：
4.8
通讯作者：
A. Cederbaum
中科院分区：
文献类型：
--
作者：
Dalibor Gergeľ;V. Mišík;K. Ondrias;A. Cederbaum
3-吗啉基丙酮亚胺（SIN-1）被广泛用于产生一氧化氮（NO）和超氧自由基（O）。SOD对SIN-1毒性的影响是复杂的，这取决于导致毒性的最终物种是什么。SIN-1（<1 mM）对HepG 2细胞只有轻微的毒性。铜、锌超氧化物歧化酶（Cu，Zn-SOD）或锰超氧化物歧化酶（Mn-SOD）可增加SIN-1的毒性。过氧化氢酶废除，而叠氮化钠增强，这种毒性，这表明H2 O2的整体机制中的关键作用。GSH从HepG 2细胞中的耗尽也增强SIN-1加SOD的毒性。虽然Me 2SO，甲酸钠，甘露醇没有保护作用，铁螯合剂，硫脲和尿酸盐保护细胞免受SIN-1加Cu，Zn-SOD介导的细胞毒性。Cu，Zn-SOD的细胞毒性作用在较低浓度（10-100单位/ml）时表现出最明显的双相剂量反应，而Mn-SOD则无此作用。在SIN-1的存在下，Mn-SOD以浓度依赖性方式增加H2 O2的积累。而Cu，Zn-SOD在低浓度时增加SIN-1对H_2O_2的积累，高浓度时增加不明显，说明高浓度的Cu，Zn-SOD与H_2O_2相互作用。EPR自旋捕集研究表明，高浓度的Cu，Zn-SOD分解H2 O2形成羟基自由基。NO供体SNAP和DEA/NO的细胞毒性作用仅被SOD轻微增强;过氧化氢酶没有影响。因此，在这些条件下负责SIN-1和SNAP或DEA/NO对HepG 2细胞的毒性的氧化剂是不同的，其中来自O歧化的H2 O2对SIN-1起主要作用。这些结果表明，SOD的SIN-1毒性的增强是由于增强生产H2 O2，然后通过过渡金属催化反应的关键细胞位点的位点特异性损伤。这些结果还强调，SOD作为一种保护剂对氧化损伤的作用是复杂的和依赖的，在一定程度上，在随后的命运和所产生的H2 O2的反应性。
3-Morpholinosydnonimine (SIN-1) is widely used to generate nitric oxide (NO) and superoxide radical (O). The effect of SOD on the toxicity of SIN-1 is complex, depending on what is the ultimate species responsible for toxicity. SIN-1 (<1 mM) was only slightly toxic to HepG2 cells. Copper, zinc superoxide dismutase (Cu,Zn-SOD) or manganese superoxide dismutase (Mn-SOD) increased the toxicity of SIN-1. Catalase abolished, while sodium azide potentiated, this toxicity, suggesting a key role for H2O2 in the overall mechanism. Depletion of GSH from the HepG2 cells also potentiated the toxicity of SIN-1 plus SOD. Although Me2SO, sodium formate, and mannitol had no protective effect, iron chelators, thiourea and urate protected the cells against the SIN-1 plus Cu,Zn-SOD-mediated cytotoxicity. The cytotoxic effect of Cu,Zn-SOD but not Mn-SOD, showed a biphasic dose response being most pronounced at lower concentrations (10-100 units/ml). In the presence of SIN-1, Mn-SOD increased accumulation of H2O2 in a concentration-dependent manner. In contrast, Cu,Zn-SOD increased H2O2 accumulation from SIN-1 at low but not high concentrations of the enzyme, suggesting that high concentrations of the Cu,Zn-SOD interacted with the H2O2. EPR spin trapping studies demonstrated the formation of hydroxyl radical from the decomposition of H2O2 by high concentrations of the Cu,Zn-SOD. The cytotoxic effect of the NO donors SNAP and DEA/NO was only slightly enhanced by SOD; catalase had no effect. Thus, the oxidants responsible for the toxicity of SIN-1 and SNAP or DEA/NO to HepG2 cells under these conditions are different, with H2O2 derived from O dismutation playing a major role with SIN-1. These results suggest that the potentiation of SIN-1 toxicity by SOD is due to enhanced production of H2O2, followed by site-specific damage of critical cellular sites by a transition metal-catalyzed reaction. These results also emphasize that the role of SOD as a protectant against oxidant damage is complex and dependent, in part, on the subsequent fate and reactivity of the generated H2O2.
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影响因子：
3.9
作者：
ISCHIROPOULOS, H;ZHU, L;BECKMAN, JS
通讯作者：
BECKMAN, JS
影响因子：
7.4
作者：
CROW, JP;SPRUELL, C;BECKMAN, JS
通讯作者：
BECKMAN, JS
DOI：
10.1073/pnas.89.20.9715
发表时间：
1992-10-15
影响因子：
11.1
作者：
OURY, TD;HO, YS;CRAPO, JD
通讯作者：
CRAPO, JD
影响因子：
3.9
作者：
E. Kukiełka;A. Cederbaum
通讯作者：
E. Kukiełka;A. Cederbaum
DOI：
--
发表时间：
1989-02
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
M. Scott;S. Meshnick;J. Eaton
通讯作者：
M. Scott;S. Meshnick;J. Eaton