ANTAGONISM OF EXPERIMENTAL CYANIDE TOXICITY IN RELATION TO THE IN VIVO ACTIVITY OF CYTOCHROME OXIDASE

¹ University of Pittsburgh, Graduate School of Public Health, Pittsburgh, Pennsylvania

The inhibition and recovery of liver cytochrome oxidase in mice, rats and gerbils were measured after the i.p. administration of potassium cyanide. The inhibition of cytochrome oxidase reached a maximum 5 to 10 min after cyanide administration, and in the mouse returned to normal activity 5 to 20 mm later, depending on dose. However, in the rat and gerbil, recovery of the enzyme after maximal inhibition was more prolonged, and, depending on dose and strain of animal, required up to 1 hr or more. Also studied were the effects of varying doses of sodium thiosulfate and sodium nitrite, given prior to or after cyanide administration, in modifying the syndrome of cyanide poisoning and accelerating the reactivation in vivo of cytochrome oxidase. Thiosulfate and nitrite were within minutes able to reactivate in vivo cyanide-induced inhibition of cytochrome oxidase when administered before or after cyanide. These drugs prevented the symptoms or lethality of cyanide when given even 1 or 2 hr prior to cyanide administration, depending on the species treated. The inhibition in spleen cytochrome oxidase by cyanide and its reversal by thiosulfate are similar to those of the liver except that the effects are somewhat slower. The ability of animals to survive divided doses of cyanide depended on the time between doses. If the second dose was administered at a time when the inhibition of cytochrome oxidase was at or near a maximum, the animals died even though the total dose when given at one time was sublethal. It appears that thiosulfate acts by penetrating the mitochondria where it furnishes sulfur to rhodanese, whereas nitrite acts extramitochondrially. The prophylactic and therapeutic actions of thiosulfate appear more effective than heretofore considered, especially relative to nitrite. This observation has important implications for treatment of cyanide poisoning in humans.

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