OXIDATIVE STRESS IN THE CYTOTOXICITY OF DITHIOCARBAMATES

该提案旨在研究 二硫代氨基甲酸酯，一类在生物医学中有许多应用的化合物， 农业和工业。有待检验的假设是， 二硫代氨基甲酸酯和单烷基二硫代氨基甲酸酯显示出共同的机理， 毒性（即，二硫化碳的释放），但后者， 更具有细胞毒性，具有涉及氧化应激的额外机制。 单烷基二硫代氨基甲酸酯可代谢为异硫氰酸酯， 巯基离子可能在细胞中起作用以增加氧化应激。 这在神经元中具有特别重要的意义， 氧化代谢率。将进行拟议的实验 主要是肝细胞。本研究的第一个目的是确定是否 单烷基二硫代氨基甲酸酯通过异硫氰酸酯发挥细胞毒性， 介导的谷胱甘肽耗竭。细胞毒性、谷胱甘肽水平和 谷胱甘肽结合物和丙二醛和蛋白质水平 将测定羰基化合物。第二个目标是确定 细胞毒性是通过抑制电子传递介导的， 巯基离子。为此，电子传递，细胞色素氧化酶 并测量ATP水平。

The proposal aims at investigating the mechanism(s) of cytotoxicity of dithiocarbamate, a class of compounds with a number of applications in agriculture and industry. The hypothesis to be tested is that dithiocarbamates and monoalkyldithiocarbamates show common mechanisms of toxicity (i.e., liberation of carbon disulfide) but that the latter, which is more cytotoxic, has an additional mechanism involving oxidative stress. Monoalkyldithiocarbamates can be metabolized to isothiocynanate and sulfhydryl ions may act in concern in cells to increase oxidative stress. This would be of particular significance in neurons, which have a high rate of oxidative metabolism. The proposed experiments will be carried out mostly in hepatocytes. The first aim of this study is to determine whether monoalkyldithiocarbamates exert cytotoxicity through isothiocyanate- mediated depletion of glutathione. Cytotoxicity, levels of glutathione and glutathione conjugates and levels of malonyldialdehyde and protein carbonyls will be determined. A second aim is to determine whether cytotoxicity is mediated by inhibition of electron transport by sulfhydryl ions. For this purpose, electron transport, cytochrome oxidase and ATP levels will be measured.