Monomethylarsonous Acid Inhibits Endothelial Nitric Oxide Synthase Activity
Monomethylarsonous Acid Inhibits Endothelial Nitric Oxide Synthase Activity
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DOI：
10.1248/jhs.51.728
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发表时间：
2005-12
影响因子：
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通讯作者：
D. Sumi;K. Taguchi;Yang Sun;Y. Shinkai;Y. Kumagai
中科院分区：
文献类型：
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作者：
D. Sumi;K. Taguchi;Yang Sun;Y. Shinkai;Y. Kumagai
无机砷在细胞中经历广泛的还原和氧化甲基化，产生无机砷单甲基亚胂酸（MMAIII）的反应性代谢产物，其对邻位硫醇具有高反应性。我们的流行病学研究在慢性砷中毒流行区和实验中暴露于砷的兔子显示，砷暴露的结果减少全身一氧化氮（NO）的生产。在这项研究中，我们研究了MMAIII对内皮型一氧化氮合酶（eNOS）活性的影响。用牛主动脉内皮细胞（BAEC）膜组分，发现MMAIII是eNOS的有效抑制剂，IC_（50）值为2.1 μM，而无机砷及其甲基化代谢产物对eNOS活性无影响。有趣的是，添加二硫苏糖醇显著阻断了MMAIII诱导的eNOS活性抑制。这份报告是第一次提出，MMAIII与eNOS蛋白相互作用，通过推测邻位硫醇，导致eNOS活性降低。
Inorganic arsenic undergoes extensive reduction and oxidative methylation in cells to yield a reactive metabolite of inorganic arsenic monomethylarsonous acid (MMAIII), which has a high reactivity toward vicinal thiols. Our epidemiological study in an endemic area of chronic arsenic poisoning and in experiments with rabbits exposed to arsenic revealed that arsenic exposure results in a reduction of systemic nitric oxide (NO) production. In this study, we examined the effect of MMAIII on endothelial NO synthase (eNOS) activity. With the membrane fraction of bovine aortic endothelial cells (BAEC), it was found that MMAIII with an IC50 value of 2.1 μM was a potent inhibitor of eNOS, whereas inorganic arsenic and their methylated metabolites had no effect on eNOS activity. Interestingly, addition of dithiothreitol markedly blocked the MMAIII-induced inhibition of eNOS activity. This report is the first to suggest that MMAIII interacts with eNOS protein through presumably vicinal thiols, leading to decreased eNOS activity.