Protective Role of Intracellular Superoxide Dismutase against Extracellular Oxidants in Cultured Rat Gastric Cells

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We examined the role of intracellular superoxide dismutase (SOD) as an antioxidant by studying the effect of diethyldithiocarbamate (DDC) on extracellular H2 O2-induced damage in cultured rat gastric mucosal cells. Chromium-51-labeled monolayers from rat stomachs were exposed to glucose oxidase-generated H2 O2 or reagent H2 O2, which both caused a dose-dependent increase in Chromium-51 release. DDC dose-dependently enhanced Chromium-51 release by hydrogen peroxide, corresponding with inhibition of endogenous SOD activity. This inhibition was not associated either with modulation of other antioxidant defenses, or with potentiation of injury by nonoxidant toxic agents. Enhanced hydrogen peroxide damage by DDC was significantly prevented by chelating cellular iron with deferoxamine or phenanthroline. Inhibition of cellular xanthine oxidase (possible source of superoxide production) by oxypurinol neither prevented lysis by hydrogen peroxide nor diminished DDC-induced sensitization to H2 O2. We conclude that (a) extracellular H2 O2 induces dose-dependent damage to cultured gastric mucosal cells; (b) intracellular SOD plays an important role in preventing H2 O2 damage; (c) generation of superoxide seems to occur intracellularly after exposure to H2 O2, but independent of cellular xanthine oxidase; and (d) cellular iron mediates the damage by catalyzing the production of more reactive species from superoxide and H2 O2, the process which causes ultimate cell injury. (J. Clin. Invest. 1994. 93:331-338.) Key words: diethyldithiocarbamate. hydrogen peroxide. hydroxyl radical. iron. superoxide anion

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