Sandy M S, Moldeus P, Ross D, Smith M T
Department of Biomedical and Environmental Health Sciences, School of Public Health, University of California, Berkeley 94720.
Arch Biochem Biophys. 1987 Nov 15;259(1):29-37. doi: 10.1016/0003-9861(87)90466-8.
Diquat is a hepatotoxin whose toxicity in vivo and in vitro is mediated by redox cycling and greatly enhanced by pretreatment with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), an inhibitor of glutathione reductase. The mechanism by which redox cycling mediates diquat cytotoxicity is unclear, however. Here, we have attempted to examine the roles of three potential products of redox cycling, namely superoxide anion radical (O2-.), hydrogen peroxide (H2O2), and hydroxyl radical (.OH), in the toxicity of diquat to BCNU-treated isolated hepatocytes. Addition of high concentrations of catalase, but not superoxide dismutase, to the incubations provided some protection against the toxic effect of diquat, but much better protection was observed when catalase was added in combination with the iron chelator desferrioxamine. Addition of desferrioxamine alone also provided considerable protection, whereas the addition of copper ions enhanced diquat cytotoxicity. Taken together, these results indicate that both H2O2 and the transition metals iron and copper could play major roles in the cytotoxicity of diquat. The role of O2-. remains less clear, however, but studies with diethylenetriaminepentaacetic acid indicate that O2-. is unlikely to significantly contribute to the reduction of Fe3+ to Fe2+. The hydroxyl radical or a related species seems the most likely ultimate toxic product of the H2O2/Fe2+ interaction, but hydroxyl radical scavengers afforded only minimal protection.
敌草快是一种肝毒素，其体内和体外毒性是由氧化还原循环介导的，并且通过用谷胱甘肽还原酶抑制剂1,3-双(2-氯乙基)-1-亚硝基脲(BCNU)预处理而大大增强。然而，氧化还原循环介导敌草快细胞毒性的机制尚不清楚。在这里，我们试图研究氧化还原循环的三种潜在产物，即超氧阴离子自由基(O2-.)、过氧化氢(H2O2)和羟基自由基(.OH)在敌草快对BCNU处理的离体肝细胞毒性中的作用。在孵育体系中加入高浓度的过氧化氢酶，而不是超氧化物歧化酶，对敌草快的毒性作用有一定的保护作用，但当过氧化氢酶与铁螯合剂去铁胺联合加入时，观察到更好的保护作用。单独加入去铁胺也提供了相当大的保护作用，而加入铜离子则增强了敌草快的细胞毒性。综上所述，这些结果表明H2O2以及过渡金属铁和铜可能在敌草快的细胞毒性中起主要作用。然而，O2-.的作用仍不太清楚，但用二乙烯三胺五乙酸进行的研究表明，O2-.不太可能显著促进Fe3+还原为Fe2+。羟基自由基或相关物质似乎是H2O2/Fe2+相互作用最可能的最终有毒产物，但羟基自由基清除剂仅提供了最小程度的保护。
