Inhibition of cellular antioxidants: a possible mechanism of toxic cell injury

Cells that utilize molecular oxygen generate highly reactive oxygen-derived free radicals. Endogenous cellular oxidants inactivate oxidant free radicals and protect aerobic cells from oxidant injury. Glutathione, glutathione reductase, and superoxide dismutase are key components of this antioxidant defense. Inhibition of antioxidant components would be expected to result in cell injury. Using exposure to oxygen at high pressure to increase the level of oxidant free radicals, evidence is presented to support the hypothesis that inhibition of cellular antioxidants renders organisms more susceptible to oxygen toxicity. Diethyldithiocarbamate at doses of 250, 500 and 1000 mg/kg inhibited rat brain superoxide dismutase activity and shortened onset time to seizures in a dose-related manner in 4 ATA oxygen. Carmustine at doses of 12.5, 25 and 50 mg/kg inhibits glutathione reductase activity in rat brain in proportion to the dose. Time to onset of seizures of rats pretreated with carmustine prior to exposure to 4 ATA oxygen was shortened, and oxidized glutathione levels were increased in the cortex and subcortex. These data suggest that inhibition of antioxidant components results in organisms becoming more sensitive to oxygen toxicity. Compounds that inhibit cellular antioxidants may produce toxic cell injury by permitting intracellular oxidant free radicals to attack essential cell constituents.