Biphasic effects of dithiocarbamates on the activity of nuclear factor-kappa B

Dithiocarbamates are well-known antioxidants and nuclear factor-kappa B (NF -kappa B) inhibitors. Recently, they have been characterized as zinc ionoph ores. Concentration-dependent biphasic effects of dithiocarbamates on NF-ka ppa B activity have been widely reported. We studied the mechanism of this phenomenon in relation to Zn2+ influx. Two dithiocarbamates, pyrrolidine di thiocarbamate and diethyldithiocarbamate, showed concentration-dependent bi phasic effects in inhibiting NF-kappa B activation in cerebral endothelial cells. These unique effects of dithiocarbamates on NF-kappa B were tightly linked to their ability to elevate intracellular Zn2+ levels. At high conce ntrations (> 500 mu M), dithiocarbamates started to lose their ability to p romote Zn2+ influx and to inhibit NF-kappa B activation. These results migh t provide insight into the appropriate use of dithiocarbamates in various d isorders. (C) 2000 Elsevier Science B.V. All rights reserved.