Department of Clinical Medicine, National Institute for Minamata Disease, 4058-18 Hama, Minamata 867-0008, Japan.
J Biol Chem. 2011 Feb 25;286(8):6641-9. doi: 10.1074/jbc.M110.168872. Epub 2010 Nov 24.
Methylmercury (MeHg) toxicity is a continuous environmental problem to human health. The critical role of oxidative stress in the pathogenesis of MeHg cytotoxicity has been clarified, but the molecular mechanisms underlying MeHg-mediated oxidative stress remain to be elucidated. Here we demonstrate a post-transcriptional effect of MeHg on antioxidant selenoenzymes by using a MeHg-susceptible cell line. MeHg-induced selenium deficiency leads to failure of the recoding of a UGA codon for selenocysteine and results in degradation of the major antioxidant selenoenzyme glutathione peroxidase 1 (GPx1) mRNA by nonsense-mediated mRNA decay (NMD), a cellular mechanism that detects the premature termination codon (PTC) located 5'-upstream of the last exon-exon junction and degrades PTC-containing mRNAs. In contrast, thioredoxin reductase 1 (TrxR1), another antioxidant selenoenzyme of the thioredoxin system, was likely skipped by NMD because of a UGA codon in the last exon. However, TrxR1 activity was decreased despite mRNA up-regulation, which was probably due to the synthesis of aberrant TrxR1 protein without selenocysteine. Changes in selenoenzyme GPx1 and TrxR1 mRNAs were observed earlier than was the incidence of oxidative stress and up-regulation of other antioxidant enzyme mRNAs. Results indicated that the MeHg-induced relative selenium-deficient condition affects the major antioxidant selenoenzymes GPx1 and TrxR1 through a post-transcriptional effect, resulting in the disturbance of cellular redox systems and the incidence of oxidative stress. Treatment with ebselen, a seleno-organic compound, effectively suppressed oxidative stress and protected cells against MeHg-induced relative selenium deficiency and cytotoxicity.
甲基汞（MeHg）毒性是对人类健康的持续环境问题。氧化应激在 MeHg 细胞毒性发病机制中的关键作用已得到阐明，但介导 MeHg 诱导的氧化应激的分子机制仍有待阐明。在这里，我们通过使用对 MeHg 敏感的细胞系证明了 MeHg 对抗氧化硒酶的转录后效应。MeHg 诱导的硒缺乏导致硒代半胱氨酸的 UGA 密码子的重编码失败，并且通过无意义介导的 mRNA 降解（NMD）导致主要抗氧化硒酶谷胱甘肽过氧化物酶 1（GPx1）mRNA 降解，这是一种检测位于最后外显子-外显子连接的 5'-上游的提前终止密码子（PTC）并降解含有 PTC 的 mRNA 的细胞机制。相比之下，另一种抗氧化硒酶硫氧还蛋白还原酶 1（TrxR1）由于最后一个外显子中的 UGA 密码子而可能被 NMD 跳过。然而，尽管 TrxR1 mRNA 上调，但 TrxR1 活性下降，这可能是由于合成了不含硒代半胱氨酸的异常 TrxR1 蛋白所致。硒酶 GPx1 和 TrxR1 mRNA 的变化早于氧化应激的发生和其他抗氧化酶 mRNA 的上调。结果表明，MeHg 诱导的相对硒缺乏状态通过转录后效应影响主要抗氧化硒酶 GPx1 和 TrxR1，导致细胞氧化还原系统紊乱和氧化应激的发生。用硒有机化合物 ebselen 处理可有效抑制氧化应激，并保护细胞免受 MeHg 诱导的相对硒缺乏和细胞毒性。
