Lauriault V V, Silva J M, O'Brien P J
Faculty of Pharmacy, University of Toronto, Ontario, Canada.
Drug Metabol Drug Interact. 1989;7(1):1-15. doi: 10.1515/dmdi.1989.7.1.1.
The copper-chelating thiol drug, diethyldithiocarbamate (DEDC) had previously been used to inhibit superoxide dismutase (SOD) and enhance oxidative stress mediated cytotoxicity. Using isolated rat hepatocytes, it was confirmed that DEDC enhances oxidative stress cytotoxicity induced by 1,4-naphthoquinone (1,4-NQ) and 1,4-naphthoquinone-2-sulphonate (1,4-NQ-2S). However, equimolar concentrations of DEDC also enhances cytotoxicity induced by benzoquinone, previously shown to cause cytotoxicity as a result of alkylation and not oxidative stress. Higher DEDC concentrations on the other hand protected against benzoquinone-induced cytotoxicity. Finally, the susceptibility of hepatocytes to quinone mediated oxidative stress cytotoxicity was not enhanced if the DEDC was removed before incubating the hepatocytes with naphthoquinone or benzoquinone. Enhanced oxidative stress cytotoxicity was only observed if the DEDC was present when hepatocytes were treated with quinones. It was concluded that DEDC forms conjugates with quinones which undergo futile redox cycling in the hepatocyte and form H2O2 as well as increase the susceptibility of hepatocytes to H2O2.
铜螯合硫醇药物二乙基二硫代氨基甲酸盐（DEDC）此前曾用于抑制超氧化物歧化酶（SOD）并增强氧化应激介导的细胞毒性。使用分离的大鼠肝细胞，证实了DEDC增强了由1,4-萘醌（1,4-NQ）和1,4-萘醌-2-磺酸盐（1,4-NQ-2S）诱导的氧化应激细胞毒性。然而，等摩尔浓度的DEDC也增强了由苯醌诱导的细胞毒性，先前已表明苯醌是由于烷基化而非氧化应激导致细胞毒性。另一方面，较高浓度的DEDC可防止苯醌诱导的细胞毒性。最后，如果在将肝细胞与萘醌或苯醌孵育之前去除DEDC，则肝细胞对醌介导的氧化应激细胞毒性的敏感性不会增强。仅当肝细胞用醌处理时存在DEDC时，才观察到氧化应激细胞毒性增强。得出的结论是，DEDC与醌形成共轭物，这些共轭物在肝细胞中经历无效的氧化还原循环并形成H2O2，同时增加肝细胞对H2O2的敏感性。
