Vol. 298, Issue 1, 103-109, July 2001

D609 Inhibits Ionizing Radiation-Induced Oxidative Damage by Acting as a Potent Antioxidant

Daohong Zhou , Christopher M. Lauderback, Tao Yu, Stephen A. Brown , D. Allan Butterfield and John S. Thompson

Division of Allergy, Immunology, and Rheumatology, Department of Internal Medicine (D.Z., T.Y., S.A.B., J.S.T.), Department of Chemistry and Center of Membrane Sciences (C.M.L., D.A.B.), University of Kentucky, Lexington, Kentucky; Veterans Administration Medical Center, Lexington, Kentucky (S.A.B., J.S.T.); and Division of Research, Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina (D.Z.)

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 -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-B. 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.