Selenium Redox Cycling in the Protective Effects of Organoselenides against Oxidant-Induced DNA Damage

Abstract

The biological role of selenium is a subject of intense current interest, and the antioxidant activity of selenoenzymes is now known to be dependent upon redox cycling of selenium within their active sites. Exogenously supplied or metabolically generated organoselenium compounds, capable of propagating a selenium redox cycle, might therefore supplement natural cellular defenses against the oxidizing agents generated during metabolism. We now report evidence that selenium redox cycling can enhance the protective effects of organoselenium compounds against oxidant-induced DNA damage. Phenylaminoethyl selenides were found to protect plasmid DNA from peroxynitrite-mediated damage by scavenging this powerful cellular oxidant and forming phenylaminoethyl selenoxides as the sole selenium-containing products. The redox properties of these organoselenoxide compounds were investigated, and the first redox potentials of selenoxides in the literature are reported here. Rate constants were determined for the reactions of the selenoxides with cellular reductants such as glutathione (GSH). These kinetic data were then used in a MatLab simulation, which showed the feasibility of selenium redox cycling by GSH in the presence of the cellular oxidant, peroxynitrite. Experiments were then carried out in which peroxynitrite-mediated plasmid DNA nick formation in the presence or absence of organoselenium compounds and GSH was monitored. The results demonstrate that GSH-mediated redox cycling of selenium enhances the protective effects of phenylaminoethyl selenides against peroxynitrite-induced DNA damage.

Antioxidant Activity of Sulfur and Selenium: A Review of Reactive Oxygen Species Scavenging, Glutathione Peroxidase, and Metal-Binding Antioxidant Mechanisms

“…Glutathione peroxidase can decompose peroxynitirite, and much work has focused on the development of organoselenium compounds capable of similar catalytic reactions [197,242,246,247]. The compounds 4,4 0 -methoxyphenyl diselenide and the corresponding selenide prevented OONO --mediated DHR-123 oxidation with IC 50 values of 0.5 and 2.38 lM, respectively, similar to the IC 50 value for ebselen (0.2 lM) [246].…”

“…The protective effects of selenomethionine were demonstrated in hippocampal neurons in rats exposed to iron/hydrogen peroxide by modulation of GPx radical scavenging activity [213]. In addition, the neuroprotective [15,53,116,[195][196][197] Methyl-selenocysteine Diet Antioxidant [116,195,198] Selenocystamine Endogenously synthesized Antioxidant [98,[198][199][200] Selenocystine Diet/endogenously synthesized Antioxidant [198,201] 3,3-Diselenobispropionic acid Synthetic Antioxidant [15,202] 3,3-Selenobispropionic acid Synthetic Antioxidant [198] Selenium dioxide Synthetic Antioxidant/pro-oxidant [13,203] Sodium selenite Environmental/diet Antioxidant/pro-oxidant [13,193,195,[203][204][205] Sodium selenate Environmental/diet No effect [13,195,203] Sodium Selenide Endogenously synthesized No effect [15,198,201,206] Ebselen Synthetic Antioxidant [54,[207][208][209][210] Methyl-N-(4-methylphenyl) Selenocarbamate Synthetic Antioxidant [211] Methyl-N-phenylselenocarbamate Synthetic Antioxidant [211] effects of ebselen hav...…”

“…In addition, several acyclic ebselen analogs prevented peroxynitrite dye oxidation of Ponceau-4R similar to ebselen itself [247]. De Silva and coworkers examined the ability of selenomethonine and several phenylamino selenoxides to inhibit peroxynitrite-mediated DNA damage, and found that these compounds inhibited 31-40% of DNA damage at 500 lM [197]. Using a similar assay, selenomethionine and selenocystine inhibited similar percentages of DNA damage at double the concentration (25.5 and 41.6%, respectively, at 1000 lM).…”

A novel polysaccharide from Se-enriched Ganoderma lucidum induces apoptosis of human breast cancer cells

“…Although several mechanisms have been proposed to account for anticancer effects of Se-containing polysaccharide, selective induction of tumor cell apoptosis may be of particular significance as chemopreventive agents (11)(12)(13)(14).…”

Role of the Alkali Labile Sites, Reactive Oxygen Species and Antioxidants in DNA Damage Induced by Methylated Trivalent Metabolites of Inorganic Arsenic

“…In summary, the present data indicate that trivalent methylated arsenic metabolites at low concentrations can induce oxidative stress associated-genotoxicity in human lymphocytes, with MMA III being more genotoxic than DMA III at low concentrations and both metabolites could induce ALS, and that this effect can be modulated by the addition of Se-Met, and less efficiently by vitamin C. This difference in the antioxidant capacity suggests that, in addition to ROS, DMA III and MMA III could generate other kinds of reactive species, such as peroxynitrite (Burdenson et al 2002) and that selenium protects the cell against this oxidant better than vitamin C (Rafferty et al 2003;De Silva et al 2004). Further studies are needed to elucidate which reactive species produce the DNA damage generated at non-cytotoxic methylated trivalent arsenic metabolites concentrations.…”