Dithiocarbamates: effects on lipid hydroperoxides and vascular inflammatory gene expression.
Dithiocarbamates are a well-defined family of antioxidants that may have therapeutic uses such as in treatment of inflammation and atherosclerosis. A critical event in the pathogenesis of atherosclerosis is the infiltration of inflammatory cells into the vessel wall. Vascular cell adhesion molecule-1 (VCAM-1) plays a pivotal role in this process by mediating leukocyte binding to endothelial cells. VCAM-1 expression is stimulated by oxidized polyunsaturated fatty acids such as 13-hydroperoxy-octadecadienoic acid (13-HPODE), 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 human endothelial cells; however, its effects on the oxidative second messenger pathway are unknown. Using a lipoxygenase (LO) inhibition assay in tandem with a colorimetric assay for lipid peroxides, we determined that PDTC does 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 inflammation and atherosclerosis.
Somers
P K
PK
AtheroGenics, Inc., Alpharetta, GA, USA.pksomers@home.com
Medford
R M
RM
Saxena
U
U
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008041:Linoleic Acids / Q000378:metabolism; D008054:Lipid Peroxides / Q000378:metabolism*; D010084:Oxidation-Reduction; D011759:Pyrrolidines / Q000494:pharmacology*; D015290:Second Messenger Systems / Q000187:drug effects; D013859:Thiocarbamates / Q000494:pharmacology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D005227:Fatty Acids; D008041:Linoleic Acids; D008054:Lipid Peroxides; D011759:Pyrrolidines; D013859:Thiocarbamates; D019010:Vascular Cell Adhesion Molecule-1; C038649:13-hydroperoxy-9,11-octadecadienoic acid; C020972:pyrrolidine dithiocarbamic acid