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 i s 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.
