USE OF CYTOCHROME-P450 MONOOXYGENASE-2 E1 ISOZYME INHIBITORS TO DELAYSEIZURES CAUSED BY CENTRAL-NERVOUS-SYSTEM OXYGEN-TOXICITY

Background: The neuronal origins and mechanisms of central nervous sys tem oxygen toxicity are only partly understood. Oxygen free radicals a re felt to play a major role in the production of CNS oxygen toxicity because of the interactions of free radicals with plasma membranes pro ducing lipid peroxidation. The cytochrome P-450 monooxygenase system I IE1 isozyme is important in the brain. This led to trials of P450 mono oxygense inhibitors for prevention of oxygen toxicity. Diethyldithioca rbonate (DDC) proved to be the most promising agent in this class; 21- aminosteroid lazeroid compounds have been successful in experimentally limiting pulmonary oxygen toxicity. This led to our trying to prevent neuronal oxygen toxicity by the use of 21-aminosteroid and six other drugs during hyperoxia. Methods: In our experiments, mice were placed in an oxygen-filled hyperbaric chamber in paired experiments. One pre- treated mouse and one control mouse were exposed simultaneously to ass ess the efficacy of drugs in preventing seizures caused by hyperbaric oxygen at 5.1 atmospheres absolute. Time to seizure was observed throu gh a port hole in the hull of the hyperbaric chamber. Results: DDC, 21 -aminosteroid and propranolol produced significant delays in the onset of seizures (p < 0.001) with no observable side effects; 1-aminobenzo triazole and disulfiram produced much shorter delays in the onset of s eizures caused by hyperbaric oxygen and also had unacceptable side eff ects.