Effects of pyrrolidine dithiocarbamate on endothelial cells: Protection against oxidative stress

The dithiocarbamates are well known for their antioxidant properties and ef fects on cellular transcriptional events. For example, pyrrolidine dithioca rbamate (PDTC) is widely used as an inhibitor of nuclear factor kappa B (NF kappa B) and this, or related compounds may have therapeutic potential in inhibiting atherosclerosis. However, the precise molecular mechanisms throu gh which PDTC could elicit antioxidant or cell signaling effects in a cellu lar setting remain unclear. Furthermore, the mechanisms for the effects of PDTC on NF kappa B are likely to involve inhibition of binding of the trans cription factor to DNA rather than an effect on the activation process as f irst proposed. In relation to pharmacological applications of such compound s, little is known of their interaction with endothelial cells, the anticip ated site of action for inhibition of vascular related diseases. Until rece ntly, PDTC was generally classified as an antioxidant but evidence for pro- oxidant effects have been reported. In this study, we have addressed this i ssue in bovine aortic endothelial cells and identified two mechanisms throu gh which PDTC can exert antioxidant effects. At low concentrations (0-25 mu M), PDTC induces a concentration dependent increase in cellular GSI-I leve ls through the increased activity of gamma-glutamylcysteine synthetase. At higher concentrations, GSH oxidation and apoptotic cell death occur. Using 2,3 dimethoxy-1,4-napthoquinone (DMNQ) as an intracellular generator of sup eroxide radicals, we find PDTC (10 mu M) protects against the cytotoxicity of this agent through a GSH-independent mechanism. (C) 1999 Elsevier Scienc e Inc.