Derivatives of xanthic acid are novel antioxidants: application to synaptosomes.
Xanthic acids have long been known to act as reducing agents. Recently, D609, a tricyclodecanol derivative of xanthic acid, has been reported to have anti-apoptotic and anti-inflammatory properties that are attributed to specific inhibition of phosphatidyl choline phospholipase C (PC-PLC). However, because oxidative stress is involved in both of these cellular responses, the possibility that xanthates may act as antioxidants was investigated in the current study. Finding that xanthates efficiently scavenge hydroxyl radicals, the mechanism by which D609 and other xanthate derivatives may protect against oxidative damage was further examined. The xanthates studied, especially D609, mimic glutathione (GSH). Xanthates scavenge hydroxyl radicals and hydrogen peroxide, form disulfide bonds (dixanthogens), and react with electrophilic products of lipid oxidation (acrolein) in a manner similar to GSH. Further, upon disulfide formation, dixanthogens are reduced by glutathione reductase to a redox active xanthate. Supporting its role as an antioxidant, D609 significantly (p < 0.01) reduces free radical-induced changes in synaptosomal lipid peroxidation (TBARs), protein oxidation (protein carbonyls), and protein conformation. Thus, in addition to inhibitory effects on PC-PLC, D609 may prevent cellular apoptotic and inflammatory cascades by acting as antioxidants and novel GSH mimics. These results are discussed with reference to potential therapeutic application of D609 in oxidative stress conditions.
Department of Chemistry and Center of Membrane Sciences, University of Kentucky, Lexington, KY 40506, USA.
Christopher M
CM
Lauderback
Jennifer
J
Drake
Daohong
D
Zhou
Janna M
JM
Hackett
Alessandra
A
Castegna
Jaroslaw
J
Kanski
Maria
M
Tsoras
Sridhar
S
Varadarajan
D Allan
DA
Butterfield
D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis; D001952:Bridged-Ring Compounds / Q000737:chemistry / Q000494:pharmacology*; D004220:Disulfides / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals; D005978:Glutathione / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000737:chemistry / Q000494:pharmacology; D017665:Hydroxyl Radical / Q000378:metabolism; D015151:Immunoblotting; D050356:Lipid Metabolism; D008956:Models, Chemical; D009636:Norbornanes; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D013574:Synaptosomes / Q000378:metabolism*; D017392:Thiobarbituric Acid Reactive Substances; D013859:Thiocarbamates; D013871:Thiones / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D013997:Time Factors; D014466:Ultraviolet Rays
D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D001952:Bridged-Ring Compounds; D004220:Disulfides; D005609:Free Radicals; D009636:Norbornanes; D017392:Thiobarbituric Acid Reactive Substances; D013859:Thiocarbamates; D013871:Thiones; D017665:Hydroxyl Radical; C046498:tricyclodecane-9-yl-xanthogenate; C004918:ethylxanthate; D006861:Hydrogen Peroxide; D005978:Glutathione; D010100:Oxygen