Nitrite-Mediated Antagonism of Cyanide Inhibition of Cytochrome c Oxidase in Dopamine Neurons

Abstract

Cyanide inhibits aerobic metabolism by binding to the binuclear heme center of cytochrome c oxidase (CcOX). Amyl nitrite and sodium nitrite (NaNO(2)) antagonize cyanide toxicity in part by oxidizing hemoglobin to methemoglobin (mHb), which then scavenges cyanide. mHb generation is thought to be a primary mechanism by which the NO(2)(-) ion antagonizes cyanide. On the other hand, NO(2)(-) can undergo biotransformation to generate nitric oxide (NO), which may then directly antagonize cyanide inhibition of CcOX. In this study, nitrite-mediated antagonism of cyanide inhibition of oxidative phosphorylation was examined in rat dopaminergic N27 cells. NaNO(2) produced a time- and concentration-dependent increase in whole-cell and mitochondrial levels of NO. The NO scavenger 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxy 3-oxide (PTIO) reversed this increase in cellular and mitochondrial NO. NO generated from NaNO(2) decreased cellular oxygen consumption and inhibited CcOX activity. PTIO reversed the NO-mediated inhibition, thus providing strong evidence that NO mediates the action of NaNO(2). Under similar conditions, KCN (20muM) inhibited cellular state-3 oxygen consumption and CcOX activity. Pretreatment with NaNO(2) reversed KCN-mediated inhibition of both oxygen consumption and CcOX activity. The NaNO(2) antagonism of cyanide was blocked by pretreatment with the NO scavenger PTIO. It was concluded that NaNO(2) antagonizes cyanide inhibition of CcOX by generating of NO, which then interacts directly with the binding of KCN x CcOX to reverse the toxicity. In vivo antagonism of cyanide by NO(2)(-) appears to be due to both generation of mHb and direct displacement of cyanide from CcOX by NO.

Acute, Sublethal Cyanide Poisoning in Mice Is Ameliorated by Nitrite Alone: Complications Arising from Concomitant Administration of Nitrite and Thiosulfate as an Antidotal Combination

“…Importantly, although they did not attribute the beneficial action to reversal of cytochrome c oxidase inhibition, Baskin et al (13) showed that the NO-donor molecule diethylamine NONOate is an effective cyanide antidote. Other groups have also shown an antagonistic effect of NO and/or nitrite toward cyanide intoxication not linked to metHb formation (37–40). It follows that the mechanism by which sodium nitrite probably ameliorates cyanide intoxication involves release of NO – certainly there are many systems in vivo able to effect the conversion of nitrite to NO in the bloodstream and vasculature (41–44).…”

Effectiveness of isosorbide dinitrate in cyanide poisoning as a function of the administration timing

“…Leavesley et al demonstrated in an animal model that addition of exogenous NO attenuated cyanide inhibition of cytochrome c oxidase [27]. The same was observed when sodium nitrite was used as the source of NO that interacted directly with the binding of potassium cyanide with cytochrome c oxidase to reverse toxicity [28]. Also, it seems as if NO protects enzymatic systems from cyanide inactivation via a mechanism involving the formation of an enzyme-nitrosyl cyanide complex [29].…”

Differential oxidative stress thresholds distinguishes cellular response to vascular occlusion and chemotoxicityin vivo

“…In addition, the binuclear center of CcOX has a high affinity for oxygen, and cyanide when present; such that CN À in the mitochondria binds the binuclear center and reduces the oxygen conversion capacity of CcOX. This results into accumulation of molecular oxygen in the mitochondria matrix during oxidative stress (Leavesley et al, 2010).…”