D609 inhibits ionizing radiation-induced oxidative damage by acting as a potent antioxidant.
Tricyclodecan-9-yl-xanthogenate (D609) has been extensively studied in biological systems and exhibits a variety of biological functions, including antiviral, antitumor, and anti-inflammatory activities. Most of these activities have been largely attributed to the inhibitory effect of D609 on phosphatidylcholine-specific phospholipase C. However, as a xanthate derivative, D609 is a strong electrolyte and readily dissociates to xanthate anions and cations of alkali metals in solution. Xanthate anions and protonated xanthic acid contain a free thiol moiety and are highly reductive. This implies that D609 and other xanthate derivatives may function as potent antioxidants. Indeed, we found that D609 inhibited the Fenton reaction-induced oxidation of dihydrorhodamine 123 in a dose-dependent manner similar to that of pyrrolidinedithiocarbamate, a well known antioxidant. In addition, D609 inhibited the formation of the alpha-phenyl-tert-butylnitrone-free radical spin adducts and lipid peroxidation of synaptosomal membranes by the Fenton reagents. Furthermore, preincubation of lymphocytes with D609 resulted in a significant diminution of ionizing radiation (IR)-induced 1) production of reactive oxygen species; 2) decrease in intracellular reduced glutathione; 3) oxidative damage to proteins and lipids; and 4) activation of nuclear factor-kappaB. Moreover, when D609 (50 mg/kg i.v.) was administered to mice 10 min prior to total body IR (6.5 and 8.5 Gy), it protected the mice from IR-induced lethality. Thus, these results indicate that D609 is a potent antioxidant and has the ability to inhibit IR-induced cellular oxidative stress.
Zhou
D
D
Division of Allergy, Immunology, and Rheumatology, Department of Internal Medicine, University of Kentucky, Lexington, Kentucky, USA. zhoud@musc.edu
Lauderback
C M
CM
Yu
T
T
Brown
S A
SA
Butterfield
D A
DA
Thompson
J S
JS
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects* / Q000528:radiation effects; D008214:Lymphocytes / Q000187:drug effects* / Q000528:radiation effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D009636:Norbornanes; D018384:Oxidative Stress / Q000187:drug effects* / Q000528:radiation effects; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000528:radiation effects; D013859:Thiocarbamates; D013871:Thiones / Q000494:pharmacology*
D000975:Antioxidants; D001952:Bridged-Ring Compounds; D016328:NF-kappa B; D009636:Norbornanes; D010726:Phosphodiesterase Inhibitors; D017382:Reactive Oxygen Species; D013859:Thiocarbamates; D013871:Thiones; C046498:tricyclodecane-9-yl-xanthogenate