Hydrogen Sulfide--Mechanisms of Toxicity and Development of an Antidote.
Hydrogen Sulfide--Mechanisms of Toxicity and Development of an Antidote.
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DOI：
10.1038/srep20831
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发表时间：
2016-02-15
影响因子：
4.6
通讯作者：
Boss GR
中科院分区：
文献类型：
--
作者：
Jiang J;Chan A;Ali S;Saha A;Haushalter KJ;Lam WL;Glasheen M;Parker J;Brenner M;Mahon SB;Patel HH;Ambasudhan R;Lipton SA;Pilz RB;Boss GR
硫化氢是一种剧毒气体，是仅次于一氧化碳的吸入性死亡原因。其毒性机制仅部分已知，并且没有针对硫化物中毒的具体治疗方法。我们在包括人诱导多能干细胞 (hiPSC) 衍生的神经元在内的多种细胞类型中发现，硫化物抑制线粒体呼吸链的复合物 IV 并诱导细胞凋亡。硫化物增加了离体小鼠心脏线粒体中羟自由基的产生以及小鼠大脑和心脏中 F2-异前列腺素的产生。维生素 B12 类似物椰酰胺可逆转硫化物的细胞毒性，并将黑腹果蝇和小鼠从致命的硫化氢气体中拯救出来。 Cobinamide 通过两种不同的机制起作用：直接逆转复合物 IV 抑制和中和硫化物产生的活性氧。我们得出的结论是，硫化物会在细胞和组织中产生高度氧化应激，而钴酰胺有望成为硫化物中毒的第一种特异性治疗方法。
Hydrogen sulfide is a highly toxic gas—second only to carbon monoxide as a cause of inhalational deaths. Its mechanism of toxicity is only partially known, and no specific therapy exists for sulfide poisoning. We show in several cell types, including human inducible pluripotent stem cell (hiPSC)-derived neurons, that sulfide inhibited complex IV of the mitochondrial respiratory chain and induced apoptosis. Sulfide increased hydroxyl radical production in isolated mouse heart mitochondria and F2-isoprostanes in brains and hearts of mice. The vitamin B12 analog cobinamide reversed the cellular toxicity of sulfide, and rescued Drosophila melanogaster and mice from lethal exposures of hydrogen sulfide gas. Cobinamide worked through two distinct mechanisms: direct reversal of complex IV inhibition and neutralization of sulfide-generated reactive oxygen species. We conclude that sulfide produces a high degree of oxidative stress in cells and tissues, and that cobinamide has promise as a first specific treatment for sulfide poisoning.