On the nature of cyanide poisoning

Labianca, Dominick A.

doi:10.1021/ed056p788

Cited by 27 publications

(20 citation statements)

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“…It has been widely accepted that the mechanism by which nitrites are antidotal to cyanide intoxication is due to the metHb-inducing activity of nitrite, leading to cyanide scavenging by subsequent metHbCN formation (33). However, it has also been pointed out that the generation of significant metHb levels lags behind the antidotal action of amyl nitrite (34) and that inorganic nitrite is still effective even if the MetHb formation is suppressed (30, 35).…”

Section: Discussionmentioning

confidence: 99%

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

Cambal

Swanson

Yuan

et al. 2011

Chem. Res. Toxicol.

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Sodium nitrite alone is shown to ameliorate sub-lethal cyanide toxicity in mice when given from ~1 hour before until 20 minutes after the toxic dose as demonstrated by the recovery of righting ability. An optimum dose (12 mg/kg) was determined to significantly relieve cyanide toxicity (5.0 mg/kg) when administered to mice intraperitoneally. Nitrite so administered was shown to rapidly produce NO in the bloodsteam as judged by the dose dependent appearance of EPR signals attributable to nitrosylhemoglobin and methemoglobin. It is argued that antagonism of cyanide inhibition of cytochrome c oxidase by NO is the crucial antidotal activity rather than the methemoglobin-forming action of nitrite. Concomitant addition of sodium thiosulfate to nitrite-treated blood resulted in the detection of sulfidomethemoblobin by EPR spectroscopy. Sulfide is a product of thiosulfate hydrolysis and, like cyanide, is known to be a potent inhibitor of cytochrome c oxidase; the effects of the two inhibitors being essentially additive under standard assay conditions, rather than dominated by either one. The findings afford a plausible explanation for an observed detrimental effect in mice associated with the use of the standard nitrite-thiosulfate combination therapy at sub-lethal levels of cyanide intoxication.

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Section: Discussionmentioning

confidence: 99%

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

Cambal

Swanson

Yuan

et al. 2011

Chem. Res. Toxicol.

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“…1 and the recently verified existence of mitochondrial nitric-oxide synthase (9), there is scope for erroneously ascribing any cyanide-resistant oxidase activity measured in mammalian mitochondria to the presence of an alternate di-iron oxidase if steps are not taken to inhibit NO production. The standard treatment for cyanide poisoning involves the intravenous injection of sodium nitrite and sodium thiosulfate (52). The presumption has been that the nitrite oxidizes hemoglobin to methemoglobin, which may then strongly bind cyanide, whereas the thiosulfate promotes enzymatic conversion of cyanide to thiocyanate ion, a much less toxic compound, in the mitochondria.…”

Section: No Cnmentioning

confidence: 99%

Reversal of Cyanide Inhibition of Cytochrome c Oxidase by the Auxiliary Substrate Nitric Oxide

Pearce

Bominaar

Hill

et al. 2003

Journal of Biological Chemistry

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Nitric oxide (NO) is shown to overcome the cyanide inhibition of cytochrome c oxidase in the presence of excess ferrocytochrome c and oxygen. Addition of NO to the partially reduced cyanide-inhibited form of the bovine enzyme is shown by electron paramagnetic resonance spectroscopy to result in substitution of cyanide at ferriheme a 3 by NO with reduction of the heme. The resulting nitrosylferroheme a 3 is a 5-coordinate structure, the proximal bond to histidine having been broken. NO does not simply act as a reversibly bound competitive inhibitor but is an auxiliary substrate consumed in a catalytic cycle along with ferrocytochrome c and oxygen. The implications of this observation with regard to estimates of steady-state NO levels in vivo is discussed. Given the multiple sources of NO available to mitochondria, the present results appear to explain in part some of the curious biomedical observations reported by other laboratories; for example, the kidneys of cyanide poisoning victims surprisingly exhibit no significant irreversible damage, and lethal doses of potassium cyanide are able to inhibit cytochrome c oxidase activity by only ϳ50% in brain mitochondria.The reactions of cytochrome c oxidase with nitric oxide (NO) have recently been the subject of renewed scrutiny (1-6) because of their emerging physiological significance (7-12). Furthermore, the discovery and functional characterization of a mitochondrial NO synthase (9, 13, 14) raises a series of questions regarding the possible regulation of the electron transport chain by NO. Several catalytic cycles have been proposed (4,6,(15)(16)(17) to explain the consumption of NO by the oxidase while turning over in the presence of cytochrome c and oxygen. Some of these cycles implicitly treat the NO as an auxiliary substrate rather than simply a competitive inhibitor, to account for the observed production of nitrite in addition to the slowing of electron transfer rate. In some cases an oxyferryl intermediate of heme a 3 is proposed and interaction of incoming NO with Cu B assumed (15, 16), whereas other schemes invoke the formation of a nitrosylheme a 3 intermediate (4,6,17). Consequently, clarification of which (if either) of the two centers of the binuclear pair, heme a 3 or Cu B , preferentially reacts with NO to form detectable derivatives should be of some value in assessing the relative likelihood of one proposed scheme over another as conditions are varied.When metalloenzymes have multiple binding sites for small molecular substrates and inhibitors, especially within the same active site domain, studies with mixed-ligand adducts can often reveal useful details of the coordination chemistry. Here we report the results of an investigation into the preferred site of NO reaction with bovine heart cytochrome c oxidase in the presence of the potent competitive inhibitor, cyanide, both under conditions of turnover and where the enzyme has been allowed to equilibrate in the presence of NO, cyanide, and reducing equivalents. The findings we report appear to be ...

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“…Such effects are expected to manifest themselves in an attenuated affinity of the Fe center for small molecules. Among these, CO and the ions CN − and N 3 − , are of particular interest, because the cytotoxicity of the CN − and N 3 − ions arises from the inhibition of C c O and resultant respiratory shutdown,7 and CO is an endogenous inhibitor of ferrohemes. The mode of CN − ion binding to the heme/Cu B site and the effect(s) of Cu B on such binding remain controversial 8.…”

Section: Equilibrium Constants K [M−1 ] For Cn− N3− Ion and Co Binmentioning

confidence: 99%

Untitled

et al. 2002

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Cytochrome c oxidase (CcO) is the enzyme that makes aerobic metabolism possible by catalyzing the final step in the respiratory electron-transfer chain-a four-electron (4 e), four-proton (4 H þ ) reduction of O 2 to water. [1, 2] Catalysis proceeds at the heterobimetallic heme/Cu B site ( Figure 1). [3] The Fe center is the site of O 2 binding, and reduction of O 2 is coupled to oxidation of Cu I B , at least under single-turnover conditions. [4, 5] One of the poorly understood questions regarding the structure±activity relationship at the heme/ Cu B site is how the heme reactivity is affected by the closely positioned, positively charged Cu B center. Such effects are expected to manifest themselves in an attenuated affinity of the Fe center for small molecules. Among these, CO and the ions CN À and N 3 À , are of particular interest, because the cytotoxicity of the CN À and N 3 À ions arises from the inhibition of CcO and resultant respiratory shutdown, [7] and CO is an endogenous inhibitor of ferrohemes. The mode of CN À ion binding to the heme/Cu B site and the effect(s) of Cu B on such binding remain controversial. [8] Likewise, contradictory results have been reported for differences in the CO affinities of the wild-type and Cu B -free mutants of terminal oxidases. [9,10] Previously, we demonstrated that the biomimetic complexes shown in Figure 1 b quantitatively reproduce the key reactivity of the heme/Cu B site [6,11] and thus allow the study of questions that are not easily addressed by working with the enzyme itself. Herein we report that the steady-state reduc-ZUSCHRIFTEN

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On the nature of cyanide poisoning

Cited by 27 publications

References 1 publication

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

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

Reversal of Cyanide Inhibition of Cytochrome c Oxidase by the Auxiliary Substrate Nitric Oxide

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