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Nitrite-mediated antagonism of cyanide inhibition of cytochrome c oxidase in dopamine neurons.
- Source :
-
Toxicological sciences : an official journal of the Society of Toxicology [Toxicol Sci] 2010 Jun; Vol. 115 (2), pp. 569-76. Date of Electronic Publication: 2010 Mar 24. - Publication Year :
- 2010
-
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.
- Subjects :
- Animals
Cell Line, Transformed
Cyclic N-Oxides pharmacology
Drug Antagonism
Electron Transport Complex IV metabolism
Free Radical Scavengers pharmacology
Hydrogen Cyanide metabolism
Imidazoles pharmacology
Neurons metabolism
Nitric Oxide metabolism
Rats
Chemical Warfare Agents toxicity
Dopamine physiology
Electron Transport Complex IV antagonists & inhibitors
Hydrogen Cyanide toxicity
Neurons drug effects
Nitric Oxide Donors pharmacology
Sodium Nitrite pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1096-0929
- Volume :
- 115
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Toxicological sciences : an official journal of the Society of Toxicology
- Publication Type :
- Academic Journal
- Accession number :
- 20335280
- Full Text :
- https://doi.org/10.1093/toxsci/kfq084