D609 inhibits ionizing radiation-induced oxidative damage by acting as a potent antioxidant

Tricyctodecan-9-yl-xanthogenate (D609) has been extensively studied in biol ogical systems and exhibits a variety of biological functions, including an tiviral, antitumor, and anti-inflammatory activities. Most of these activit ies have been largely attributed to the inhibitory effect of D609 on phosph atidylcholine-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 xanth ic acid contain a free thiol moiety and are highly reductive. This implies that D609 and other xanthate derivatives may function as potent antioxidant s. Indeed, we found that D609 inhibited the Fenton reaction-induced oxidati on of dihydrorhodamine 123 in a dose-depend ent manner similar to that of p yrrolidinedithiocarbamate, a well known antioxidant. In addition, D609 inhi bited the formation of the alpha -phenyl-tert-butylnitrone-free radical spi n adducts and lipid peroxidation of synaptosomal membranes by the Fenton re agents. Furthermore, preincubation of lymphocytes with D609 resulted in a s ignificant diminution of ionizing radiation (IR)-induced 1) production of r eactive oxygen species; 2) decrease in intracellular reduced glutathione; 3 ) oxidative damage to proteins and lipids; and 4) activation of nuclear fac tor-KB. 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-ind uced lethality. Thus, these results indicate that D609 is a potent antioxid ant and has the ability to inhibit IR-induced cellular oxidative stress.