Effect of inhibition of glutathione reductase by carmustine on central nervous system oxygen toxicity.

Exposure of animals to O2 at increased partial pressures above 2.5 atmospheres absolute results in seizures. The endogenous intracellular antioxidant defense mechanisms are thought to play a protective role in mitigating such seizures. Investigations were carried out to determine if inhibiting brain glutathione reductase with carmustine would result in an alteration in time to seizures of rats exposed to high pressure O2. Treatment of air-breathing rats with carmustine (12.5, 25 and 50 mg/kg i.v.) resulted in a dose-dependent decrease (P less than .001) in whole-brain glutathione reductase activity without affecting the activities of the other components of the antioxidant defense mechanisms determined. This treatment also resulted in a dose-dependent decrease (P less than .001) in time to seizure of rats exposed to four atmospheres absolute O2. Conversely, treatment of rats with lomustine (30 mg/kg i.v.), a nitrosourea compound related to carmustine, failed to affect the activity of brain glutathione reductase or any other component of the antioxidant defense mechanism determined, or did it influence the seizure time of rats exposed to four atmospheres absolute O2. These results suggest that glutathione reductase is an integral component of the antioxidant defense mechanisms. Inhibition of this enzyme results in an alteration in sensitivity of the organism to the toxic effects of O2.