One- Versus Two-Electron Transfers: Cytotoxic and Cytoprotective Effects of Seleno-Organic Catalysts

Abstract

Abstract Reliable predictions of cytotoxic effects are often missing in the design of selenium-containing mimics of glutathione peroxidase (GPx). Our data support the concept that a major factor of toxicity is the ability of either alkyl-selenolates, arylselenolates or arylselenenylsulfides to behave as catalysts for the reductive activation of dioxygen. Model studies of selenocystamine and 7-nitro-3,3-dimethyl-benziso-(2H)-selenazoline demonstrate that undesirable one-electron transfers to dioxygen can arise either from the production of electron-rich selenolates, or from the monovalent reduction of electron-deficient selenenyl-sulfide species by flavin enzymes or by ascorbate, in the presence of glutathione GSH. We have compared the effects of five selenoaromatic GPx mimics on Jurkat cells, and we conclude that toxic effects increase with GSH oxidase activity, whereas protective effects increase with GPx activity. Thus, minimizing 1-electron transfers to dioxygen while maximizing 2-electron transfer from selenolates to hydroperoxide, would help in the design of cytoprotective catalysts. Keywords: Selenium toxicityglutathione peroxidase mimicsoxygen reductionsuperoxidehydrogen peroxideglutathioneascorbate