Faculty of Pharmacy, Meijo University.
J Toxicol Sci. 2020;45(10):619-624. doi: 10.2131/jts.45.619.
Manganese (Mn) poisoning may result in a neurological disorder called manganism. Although the neurotoxic mechanism of Mn is unclear, oxidative stress may be involved based on the interactions between neurotransmitter catecholamines and metals such as iron. Here, we propose a novel mechanism in which Mn oxidizes catecholamines and inhibits cellular transcription. Mn accelerated the oxidation of adrenaline (Ad) and produced adrenochrome (AdC) more effectively than iron. Furthermore, the oxidation of DNA bases increased when Ad, Mn, and iron were present. However, despite the absence of iron, cell viability decreased in the presence of AdC or Ad with Mn, which suggests there is another mechanism independent of oxidative DNA damage. AdC or preincubated Ad with Mn reduced mRNA synthesis in T7 RNA polymerase-driven transcription. RNA synthesis decreased in AdC-treated cells dose-dependently. These results show that Mn disrupts neuronal function via catecholamine oxidation-mediated transcriptional inhibition.
锰（Mn）中毒可能导致一种称为锰中毒的神经紊乱。尽管锰的神经毒性机制尚不清楚，但根据神经递质儿茶酚胺与铁等金属之间的相互作用，氧化应激可能与之相关。在这里，我们提出了一种新的机制，即 Mn 氧化儿茶酚胺并抑制细胞转录。Mn 加速肾上腺素（Ad）的氧化，比铁更有效地产生肾上腺素红（AdC）。此外，当 Ad、Mn 和铁存在时，DNA 碱基的氧化增加。然而，尽管没有铁，在 AdC 或 Mn 存在下的 Ad 存在时，细胞活力下降，这表明存在一种不依赖于氧化 DNA 损伤的其他机制。AdC 或用 Mn 预孵育的 Ad 降低了 T7 RNA 聚合酶驱动的转录中的 mRNA 合成。AdC 处理的细胞中 RNA 合成呈剂量依赖性下降。这些结果表明，Mn 通过儿茶酚胺氧化介导的转录抑制破坏神经元功能。
