The effects of cyanide on brain mitochondrial cytochrome oxidase and respiratory activities

Brain mitochondrial cytochrome oxidase and respiratory activities were compared after in vivo and in vitro exposure to cyanide. For the in vivo studies, mice were exposed to a non-lethal (4 mg kg-1) or lethal (20 mg kg-1) dose of KCN. From these mice, purified brain mitochondria were prepared and cytochrome oxidase and respiratory activities measured. Results of these experiments revealed greater inhibition of cytochrome oxidase activity following a lethal (20 mg kg-1) than a non-lethal (4 mg kg-1) KCN dose (57 and 45% inhibition, respectively). Respiration states 3 and 4 of brain mitochondria prepared from mice that received 4 mg kg-1 KCN were inhibited by 15 and 20%, respectively. In mice that received a lethal 20 mg kg-1 KCN dose, respiration states 3 and 4 were each inhibited by ca. 30% (P < 0.05). In vitro, mitochondrial cytochrome oxidase activity was inhibited in a concentration-dependent fashion at cyanide concentrations of 10(-6)-10(-2) M. A biphasic inhibition of ADP-stimulated (state 3) respiration was observed. Cyanide concentrations of 10(-6)-10(-4) M produced only a 25% inhibition of respiration state 3, whereas 10(-3) M produced 80% inhibition. Because this dramatic inhibition only occurred at cyanide concentrations that caused > 50% inhibition of mitochondrial cytochrome oxidase activity, these findings suggest that a large proportion of cytochrome oxidase activity may be functional reserve and that cyanide poisoning likely involves other mechanisms in addition to inhibition of cytochrome oxidase.