TY - JOUR T1 - D609 Inhibits Ionizing Radiation-Induced Oxidative Damage by Acting as a Potent Antioxidant JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 103 LP - 109 VL - 298 IS - 1 AU - Daohong Zhou AU - Christopher M. Lauderback AU - Tao Yu AU - Stephen A. Brown AU - D. Allan Butterfield AU - John S. Thompson Y1 - 2001/07/01 UR - http://jpet.aspetjournals.org/content/298/1/103.abstract N2 - 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 α-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-κB. 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. The American Society for Pharmacology and Experimental Therapeutics ER -