Dithiocarbamates: Effects on lipid hydroperoxides and vascular inflammatory gene expression

Dithiocarbamates are a well-defined family of antioxidants that may have th erapeutic uses such as in treatment of inflammation and atherosclerosis. A critical event in the pathogenesis of atherosclerosis is the infiltration o f inflammatory cells into the vessel wall. Vascular cell adhesion molecule- 1 (VCAM-1) plays a pivotal role in this process by mediating leukocyte bind ing to endothelial cells. VCAM-1 expression is stimulated by oxidized polyu nsaturated fatty acids such as 13-hydroperoxy-octadecadienoic acid (13-HPOD E), and this lipid hydroperoxide has been proposed to be a second messenger for induction of VCAM-1 gene expression. Pyrrolidine dithiocarbamate (PDTC ) markedly represses cytokine-induced VCAM-1 gene expression in cultured hu man endothelial cells; however, its effects on the oxidative second messeng er pathway are unknown. Using a lipoxygenase (LO) inhibition assay in tande m with a colorimetric assay for lipid peroxides, we determined that PDTC do es not inhibit the enzymatic oxidation of linoleic acid to 13-HPODE by LO, but directly interacts with and chemically reduces 13-HPODE. We hypothesize that dithiocarbamates may intercept the oxidative second-messenger-induced expression of VCAM-1 and other redox-regulated genes important in inflamma tion and atherosclerosis. (C) 2000 Elsevier Science Inc.