Interaction of Cyanide and Nitric Oxide with Cytochrome c Oxidase: Implications for Acute Cyanide Toxicity

Abstract

Acute cyanide toxicity is attributed to inhibition of cytochrome c oxidase (CcOX), the oxygen-reducing component of mitochondrial electron transport; however, the mitochondrial action of cyanide is complex and not completely understood. State-3 oxygen consumption and CcOX activity were studied in rat N27 mesencephalic cells to examine the functional interaction of cyanide and nitric oxide (NO). KCN produced a concentration-dependent inhibition of cellular respiration. Cyanide's median inhibitory concentration (IC50) of oxygen consumption (13.2 +/- 1.8microM) was higher than the CcOX IC50 (7.2 +/- 0.1microM). Based on respiratory threshold analysis, 60% inhibition of CcOX was necessary before oxygen consumption was decreased. Addition of high levels of exogenous NO (100microM S-nitroso-N-acetyl-DL-penicillamine) attenuated cyanide inhibition of both respiration and CcOX. On the other hand, when endogenous NO generation was blocked by an NOS inhibitor (N(omega)-monomethyl-L-arginine ester), the cyanide IC50 for both respiration and CcOX increased to 59.6 +/- 0.9microM and 102 +/- 10microM, respectively, thus showing constitutive, low-level NO production enhanced cyanide inhibition. Laser scanning cytometry showed that cyanide elevated mitochondrial NO, which then was available to interact with CcOX to enhance the inhibition. It is concluded that the rapid, potent action of cyanide is due in part to mitochondrial generation of NO, which enhances inhibition of CcOX. At low mitochondrial oxygen tensions, the cyanide-NO interaction would be increased. Also, the antidotal action of sodium nitrite is partly explained by generation of high mitochondrial levels of NO, which antagonizes the CcOX inhibition.

In Vivo Brain Oxidative Stress Model Induced by Microinjection of Sodium Nitroprusside in Mice

“…It has been suggested that the pentacyano nitroxide radical [Fe(CN) 5 ,NO] 3− of SNP rapidly releases a single cyanide ion (11). CN − has been reported to react readily with cytochrome enzymes in mitochondria, which consequently causes inhibition of cellular respiration, reduction of ATP production, and cytotoxicity (24,25). On the other hand, several other reports have recently suggested that cyanide ion has no important role in SNP-induced cytotoxicity, using in vivo and in vitro experiments (4,5).…”

Cyanide-Induced Apoptosis of Dopaminergic Cells Is Promoted by BNIP3 and Bax Modulation of Endoplasmic Reticulum-Mitochondrial Ca2+ Levels

“…Selective degeneration of dopaminergic basal ganglia pathways have been reported (Rosenberg et al, 1989;Rosenow et al, 1995). The primary action of cyanide is inhibition of cytochrome c oxidase in complex IV of the oxidative phosphorylation chain, thereby blocking intracellular oxygen utilization (histotoxic hypoxia) and reducing cellular ATP generation (Leavesley et al, 2008). The central nervous system has a limited anaerobic metabolic capacity and high energy dependence, making it one of the most susceptible organs to cyanide toxicity.…”

Mitochondrial Dysfunction and Redox Imbalance as a Diagnostic Marker of “Free Radical Diseases”

“…For ex-ample, cyanide as an inhibitor of complex IV binds to the cytochrome c oxidase heme a3-CuB binuclear center to inhibit oxygen utilization in cells and compromises the oxidative phosphorylation and ATP synthesis (62)(63)(64). As a result of cytochrome c oxidase inhibition, a cascade of reactions is initiated, which leads to mitochondrial electron transport inhibition and overproduction of ROS at complexes I and III (65). Rotenone, cyanide, myxothiazol and oligomycin significantly inhibit resting background K + by simulating the effects of hypoxia, in which leads to membrane depolarization (59).…”