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. 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. 37 references, 4 figures, 2 tables.
- Research Organization:
- Medical College of Pennsylvania, Philadelphia
- OSTI ID:
- 5705946
- Journal Information:
- Environ. Health Perspect.; (United States), Vol. 57
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
ANIMAL CELLS
INJURIES
ANTIOXIDANTS
INHIBITION
CARBAMATES
BIOLOGICAL EFFECTS
NITROSOUREAS
RATS
SENSITIVITY
SUPEROXIDE DISMUTASE
ENZYME ACTIVITY
DOSE-RESPONSE RELATIONSHIPS
GLUTATHIONE
OXYGEN
RADICALS
ANIMALS
CARBONIC ACID DERIVATIVES
CARBOXYLIC ACID SALTS
DRUGS
ELEMENTS
ENZYMES
MAMMALS
NITROSO COMPOUNDS
NONMETALS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
OXIDOREDUCTASES
PEPTIDES
POLYPEPTIDES
PROTEINS
RADIOPROTECTIVE SUBSTANCES
RODENTS
VERTEBRATES
560305* - Chemicals Metabolism & Toxicology- Vertebrates- (-1987)