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Ethanol induces peroxynitrite-mediated toxicity through inactivation of NADP~+-dependent isocitrate dehydrogenase and superoxide dismutase

机译:乙醇通过失活依赖NADP〜+的异柠檬酸脱氢酶和超氧化物歧化酶诱导过氧亚硝酸盐介导的毒性

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It has been reported that chronic alcohol administration increases peroxynitrite hepatotoxicity by enhancing concomitant production of nitric oxide and superoxide. Several studies have shown the importance of superoxide dismutase (SOD) in protecting cells against ethanol-induced oxidative stress. Recently, we demonstrated that the control of cytosolic and mitochondrial redox balance and the cellular defense against oxidative damage is one of the primary functions of NADP~+-dependent isocitrate dehydrogenase (ICDH) through to supply NADPH for antioxidant systems. In this report, we demonstrate that ethanol induces the peroxynitrite-mediated cytotoxicity in HepG2 cells through inactivation of antioxidant enzymes such as ICDH and SOD. Upon exposure to 100 mM ethanol for 3 days to HepG2 cells, a significant decrease in the viability and activities of ICDH and SOD was observed. The ethanol-induced inactivation of antioxidant enzymes resulted in the cellular oxidative damage and modulation of redox status as well as mitochondrial dysfunction in HepG2 cells. The cytoxicity of ethanol and inactivation of antioxidant enzymes were effectively protected by manganeses(III) tetrakis(N-methyl-2-pyridyl) porphyrin, a manganese SOD mimetic, and N'-monomethyl-L-arginine, a nitric oxide synthase inhibitor. These results indicate that ethanol toxicity is mediated by peroxynitrite and the peroxynitrite-mediated damage to ICDH and SOD may be resulted in the perturbation of the cellular antioxidant defense systems and subsequently lead to a pro-oxidant condition.
机译:据报道,长期饮酒会增加一氧化氮和超氧化物的同时产生,从而增加过氧亚硝酸盐的肝毒性。多项研究表明,超氧化物歧化酶(SOD)在保护细胞免受乙醇诱导的氧化应激中的重要性。最近,我们证明控制胞质和线粒体氧化还原平衡以及抵抗氧化损伤的细胞防御作用是NADP〜+依赖性异柠檬酸脱氢酶(ICDH)的主要功能之一,可为抗氧化剂系统提供NADPH。在本报告中,我们证明乙醇通过灭活抗氧化剂酶(如ICDH和SOD)在HepG2细胞中诱导过氧亚硝酸盐介导的细胞毒性。在HepG2细胞中暴露于100 mM乙醇3天后,观察到ICDH和SOD的活力和活性显着下降。乙醇诱导的抗氧化酶的失活导致HepG2细胞的细胞氧化损伤和氧化还原状态的调节以及线粒体功能障碍。锰的SOD模拟物四(N-甲基-2-吡啶基)卟啉锰和一氧化氮合酶抑制剂N'-单甲基-L-精氨酸可有效保护乙醇的细胞毒性和抗氧化酶的失活。这些结果表明乙醇毒性是由过氧亚硝酸盐介导的,并且过氧亚硝酸盐介导的对ICDH和SOD的破坏可能导致细胞抗氧化剂防御系统的紊乱,并随后导致促氧化剂状态。

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