Cytolethality of glutathione conjugates with monomethylarsenic or dimethylarsenic compounds
Cytolethality of glutathione conjugates with monomethylarsenic or dimethylarsenic compounds
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DOI：
10.1248/bpb.28.1827
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发表时间：
2005-10-01
影响因子：
2
通讯作者：
Himeno, S
中科院分区：
文献类型：
--
作者：
Kojima, C;Sakurai, T;Himeno, S
已知砷剂对人体有毒和致癌。无机砷在酶催化下甲基化为甲基胂酸（MMAsv）和二甲基胂酸（DMAsv），这是五价甲基砷的主要代谢产物。近年来的研究表明，三价甲基砷化合物是无机砷化合物甲基化后产生的，参与砷中毒。在甲基化过程中，三价甲基砷可以砷-谷胱甘肽结合物的形式产生，如单甲基砷化二谷胱甘肽（MMAs“DG）和二甲基砷化谷胱甘肽（DMAs”G）。还原型谷胱甘肽（GSH）在体外可还原MMAsv和DMAsv，产生MMAs“DG和DMAs”G。一些研究表明，外源性GSH在体外增加了MMAsv和DMAsv的细胞致死率，而另一些研究表明，外源性GSH降低了它们。在本研究中，我们通过研究不同浓度的MMAsv或DMAsv与GSH之间的反应，考察了外源性GSH对MMAsv和DMAsv细胞致死性的真实影响。当GSH超过25 mm时，GSH显著增加细胞致死性和五价甲基砷的细胞摄取，并且这种细胞致死性可能是由砷-GSH缀合物的产生引起的。然而，GSH在小于25毫米不影响细胞致死率和五价甲基砷的细胞摄取。这些发现表明，需要高浓度的砷和GSH才能形成砷-GSH结合物并显示出显着的细胞致死性。此外，我们推测MMAs“DG和DMAs”G可能分离成三价甲基砷和谷胱甘肽，然后转运到细胞中，在那里它们显示出显著的细胞致死性。
Arsenicals are known to be toxic and carcinogenic in humans. Inorganic arsenicals are enzymatically methylated to monomethylarsonic acid (MMAsv) and dimethylarsinic acid (DMAsv), which are the major pentavalent methyl arsenic metabolites. Recent reports indicate that trivalent methyl arsenicals are produced through methylation of inorganic arsenicals and participate in arsenic poisoning. Trivalent methyl arsenicals may be generated as arsenical-glutathione conjugates, such as monomethylarsonous diglutathione (MMAs'"DG) and dimethylarsinous glutathione (DMAs"'G), during the methylation process. It has been well known that reduced glutathione (GSH) reduces MMAsv and DMAsv in vitro, and produces MMAs"'DG and DMAs'"G. Some studies have shown that exogenous GSH increased cytolethality of MMAsv and DMAsv in vitro, while other studies have suggested that exogenous GSH decreased them. In this study, we examined the true effects of exogenous GSH on the cytolethality of MMAsv and DMAsv by investigating reactions between various concentrations of MMAsv or DMAsv and GSH. GSH significantly increased the cytolethality and cellular uptake of pentavalent methyl arsenicals when GSH over 25 mm was pre-incubated with mm levels of arsenicals, and this cytolethality might have been caused by arsenical-GSH conjugate generation. However, GSH at less than 25 mm did not affect the cytolethality and cellular uptake of pentavalent methyl arsenicals. These findings suggest that high concentrations of arsenicals and GSH are needed to form arsenical-GSH conjugates and to show significant cytolethality. Furthermore, we speculated that MMAs"'DG and DMAs"'G may separate into trivalent methyl arsenicals and glutathione, which are then transported into cells where they show significant cytolethality.