Selenium redox cycling in the protective effects of organoselenides against oxidant-induced DNA damage.
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.
School of Chemistry and Biochemistry and the Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, Georgia 30332-0400, USA.
Veronica
V
De Silva
Michelle M
MM
Woznichak
Kristi L
KL
Burns
Kathryn B
KB
Grant
Sheldon W
SW
May
D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology; D003198:Computer Simulation; D004247:DNA / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D004249:DNA Damage; D005021:Ethylamines / Q000737:chemistry / Q000494:pharmacology; D005978:Glutathione / Q000737:chemistry / Q000378:metabolism; D016566:Organoselenium Compounds / Q000737:chemistry / Q000494:pharmacology*; D016877:Oxidants / Q000737:chemistry / Q000633:toxicity*; D010084:Oxidation-Reduction; D030421:Peroxynitrous Acid / Q000737:chemistry / Q000633:toxicity; D010957:Plasmids / Q000737:chemistry / Q000187:drug effects / Q000235:genetics; D011199:Potentiometry; D012643:Selenium / Q000737:chemistry*
D000975:Antioxidants; D005021:Ethylamines; D016566:Organoselenium Compounds; D016877:Oxidants; D030421:Peroxynitrous Acid; C056035:phenyl-2-aminoethylselenide; D004247:DNA; D005978:Glutathione; D012643:Selenium