A novel interaction of diethyldithiocarbamate with the glutathione/glutathione peroxidase system.
Diethyldithiocarbamate (DDC) exhibits a variety of pharmacologic activities, including both radioprotective and sensitizing properties. Since the glutathione/glutathione peroxidase system may be a significant factor in determining radiation sensitivity, the potential mechanisms of action of DDC in relation to this system were examined in vitro. The interaction of DDC with reduced glutathione (GSH) was tested using a simple system based on the reduction of cytochrome c. When DDC (0.005 mM) was incubated with GSH (0.5 mM), the reduction of cytochrome c was eightfold greater than that expected from an additive effect of DDC and GSH. GSH could be replaced by oxidized glutathione and glutathione reductase. Cytochrome c reduced by DDC was oxidized by mitochondria. The interaction of DDC with both the hexosemonophosphate shunt pathway and the mitochondrial respiratory chain suggests the possibility of linking these two pathways through DDC. Oxidation of DDC by peroxide and reversal by GSH indicated that the drug can engage in a cyclic reaction with peroxide and GSH. This was confirmed when DDC was used in the assay system for glutathione peroxidase (GSHPx) without GSHPx. DDC at a concentration of 0.25 mM was more active than 0.01 unit of pure GSHPx in eliminating peroxide, and much more active than the other sulfhydryl compounds tested. These studies indicate that DDC can supplement GSHPx activity or substitute for it in detoxifying peroxides, and suggests a unique role in the chemical modification of radiation sensitivity.
D000818:Animals; D003574:Cytochrome c Group / Q000378:metabolism; D004050:Ditiocarb / Q000494:pharmacology*; D005978:Glutathione / Q000494:pharmacology*; D066298:In Vitro Techniques; D051379:Mice; D008930:Mitochondria, Liver / Q000201:enzymology; D011837:Radiation-Protective Agents / Q000494:pharmacology; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology
D003574:Cytochrome c Group; D011837:Radiation-Protective Agents; D011838:Radiation-Sensitizing Agents; D004050:Ditiocarb; D005978:Glutathione