title: Diethyldithiocarbamate (DEDC) enhances quinone mediated oxidative stress cytotoxicity in isolated hepatocytes by forming toxic quinone conjugates.
abstract: 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.
authors.affiliation: Faculty of Pharmacy, University of Toronto, Ontario, Canada.
authors.forename: V V
authors.initials: VV
authors.lastname: Lauriault
authors.forename: J M
authors.initials: JM
authors.lastname: Silva
authors.forename: P J
authors.initials: PJ
authors.lastname: O'Brien
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects*; D004050:Ditiocarb / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000166:cytology* / Q000187:drug effects; D008297:Male; D009285:Naphthoquinones / Q000494:pharmacology; D010084:Oxidation-Reduction; D011809:Quinones / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors
chemical_list: D009285:Naphthoquinones; D011809:Quinones; D004050:Ditiocarb; D013482:Superoxide Dismutase; D005978:Glutathione; C035342:1,4-naphthoquinone