Thinking about cyanide in foods

[Guest guest]

Listmates,

It has been a long time since we discussed the early work in the sulfur

chemistry that was done by Rosemary Waring at the University of Birmingham.

The following urinary values were reported in Dr. Waring's paper Sulphur

metabolism in Autism from the Journal of Nutritional and Environmental

Medicine (2000) 10, 25-32:

Autism(n=232) Controls (n=68)

Protein 103.2 64.5

Sulphite 106.9 7.1

Thiosulphate 130.8 18.6

Thiocyanate 6.4 44.0

Sulphate 6819.0 3030.8

Her paper talked about rhodanese in these words:

>The raised levels of urinary thiosulphate and reduced thiocyanate may also

>suggest a reduction in rhodanese activity. This enzyme detoxifies cyanide

>ions by combination

>with thiosulphate to form thiocyanate (see Figure 1) and has been

>relatively little

>studied. Cyanide ions are toxic; they inhibit the processes of oxidative

>phosphorylation and

>cellular oxidation reducing the adenosine triphosphate (ATP) supply in

>vivo. As brain tissue

>is very energy-demanding, the lower levels of ATP, the main supply of

>chemical energy,

>can lead to cell damage and death so that low levels of cyanide ions act

>as chronic

>neurotoxins. Again, mutations in this enzyme or inhibition of its activity

>may be part of the

>aetiology of autism.

An article below explains:

>The reactions of cyanide with metals are reversible and exhibit

>concentration-dependent equilibria, but the reactions of cyanide with

>sulfur-containing compounds are catalyzed by the enzyme rhodanese (EC

>2.8.I.1) and are essentially one-way and irreversible. The rate-limiting

>factor in the rhodanese-mediated reactions is usually the availability of

>sulfur donors in the body.

Of course, we have been concerned that the sulfur chemistry is not adequate

in autism for reasons that we don't understand all that well, unless it

comes from depletion from excesses of toxicity or too much immune activation.

What Dr. Waring did not talk about in this paper is the expected effect of

this weak step on cobalamin metabolism. Cobalamin is used by the body to

detox cyande, and it may get called upon to do that more in someone with a

deficiency in the function of rhodanese. That might up the requiirement

for other forms of cobalamin and may be a reason we see benefits from

giving various forms of cobalamin. Maybe we should be looking for the

formation of ( -CH3)( -CN)Cbl as evidence that such a process is going on

when we give methylB12.

I've put more discusions of this issue below and more discussion of

cyanide's toxicity.

Some of the grains or seeds or nuts we make flour from in g/f diets may

increase our consumption of cyanide, especially the bean flours.. I hope I

can find a lab that can test for this factor in commercial flours that we

might use. I am a little concerned that some of our low oxalate diet flour

substitutions may increase our exposure to cyanide without our knowing its

cyanide status. That would make people lean more heavily on rhodanese and

the sulfur chemistry and the cobalamins. There is some discussion of the

US making growers select varieties with lower cyanide, but I don't know if

that regulation goes into these specialty flours.

At this point, until we know, I think we might need to be cautious about

using a lot of the alternative flours, or at least we need to observe the

children with autism carefully when they eat these flours.

Thoughts?

The reaction between methylcobalamin and cyanide revisited

J. Brodiea, 1, G. Cregana, Rudi van Eldikb and Nicola E.

Brasch[], [], a

a Research School of Chemistry, Institute of Advanced Studies, Australian

National University, Canberra, ACT 0200, Australia b Institute for

Inorganic Chemistry, University of Erlangen-Nürnberg, Egerlandstrasse 1,

91058, Erlangen, Germany

Received 10 July 2002;

accepted 5 October 2002. ;

Available online 3 May 2003.

References and further reading may be available for this article. To view

references and further reading you must purchase this article.

Abstract

The reaction between the vitamin B12 coenzyme methylcobalamin and cyanide

has been re-investigated by UV–Vis and 1H NMR spectroscopies under the same

conditions. On the basis of the results and recent results of other studies

on the reaction between other alkylcobalamins and cyanide, the changes in

the 1H NMR chemical shifts and linewidths in the aromatic region observed

upon addition of cyanide to methylcobalamin can be attributed to the rapid

formation of ( -CH3)( -CN)Cbl , rather than the formation of MeCbl·CN as

proposed earlier (Inorg. Chem. 36 (1997) 4891). There is excellent

agreement between the equilibrium constant for formation of ( -CH3)(

-CN)Cbl determined by the two methods (0.35±0.03 M 1 and 0.31±0.01 M 1 from

the UV–Vis and 1H NMR spectroscopic data, respectively (D2O, pD 12.1, 25.0

°C)).

Graphical Abstract

The cause of the changes in the chemical shifts and line widths of the 1H

NMR spectrum of methylcobalamin upon the addition of cyanide has been

re-investigated.

[]

Ann Emerg Med. 2007 Jun;49(6):806-13. Epub 2006 Nov 13.[] Links

Comment in:

Ann Emerg Med. 2007 Jun;49(6):814-6.

Ann Emerg Med. 2008 Mar;51(3):338-9.

Sodium thiosulfate or hydroxocobalamin for the empiric treatment of cyanide

poisoning?

Hall AH, Dart R, Bogdan G.

Toxicology Consulting and Medical Translating Services, Inc., Elk Mountain,

WY 82324, USA. ahalltoxic@...

Cyanide poisoning must be seriously considered in victims of smoke

inhalation from enclosed space fires; it is also a credible terrorism

threat agent. The treatment of cyanide poisoning is empiric because

laboratory confirmation can take hours or days. Empiric treatment requires

a safe and effective antidote that can be rapidly administered by either

out-of-hospital or emergency department personnel. Among several cyanide

antidotes available, sodium thiosulfate and hydroxocobalamin have been

proposed for use in these circumstances. The evidence available to assess

either sodium thiosulfate or hydroxocobalamin is incomplete. According to

recent safety and efficacy studies in animals and human safety and

uncontrolled efficacy studies, hydroxocobalamin seems to be an appropriate

antidote for empiric treatment of smoke inhalation and other suspected

cyanide poisoning victims in the out-of-hospital setting. Sodium

thiosulfate can also be administered in the out-of-hospital setting. The

efficacy of sodium thiosulfate is based on individual case studies, and

there are contradictory conclusions about efficacy in animal models. The

onset of antidotal action of sodium thiosulfate may be too slow for it to

be the only cyanide antidote for emergency use. Hydroxocobalamin is being

developed for potential introduction in the United States and may represent

a new option for emergency personnel in cases of suspected or confirmed

cyanide poisoning in the out-of-hospital setting.

PMID: 17098327 [PubMed - indexed for MEDLINE]

Toxicology. 1979 Sep;14(1):81-90.[] Links

Effects of low cobalamin diet and chronic cyanide toxicity on cobalamin

distribution in baboons.

Linnell JC, J, Crampton RF, WT, Knowles JF, Gaunt IF, Wise IJ,

s DM.

This paper reports the bodily distribution of total cobalamin and

individual cobalamins at the termination of an experiment on the effects of

a low cobalamin diet and chronic cyanide or thiocyanate administration in

baboons. The results show that the distribution of cobalamins in the

tissues of the baboon can be altered by a low cobalamin diet and also by

chronic intoxication with cyanide, whether or not the animals are on a low

cobalamin diet. All animals on the low cobalamin diet showed a reduction in

total and individual cobalamins. In blood plasma and erythrocytes, kidney,

spleen, testis and brain, the proportion of methylcobalamin tended to be

disproportionately reduced in cobalamin-depleted animals. This reduction

was lessened or prevented by the administration of cyanide. Neither cyanide

not thiocyanate produced a significant increase in the proportion of

cyanocobalamin in plasma, though thiocyanate produced a large increase in

cyanocobalamin in erythrocytes. In liver, cyanocobalamin was more than

doubled by the administration of cyanide to cobalamin-depleted animals.

PMID: 119336 [PubMed - indexed for MEDLINE]

Inorg Chem. 1997 Jul 16;36(15):3216-3222.[] Links

Evidence for the Unexpected Associative Displacement of Adenosyl by Cyanide

in Coenzyme B(12).

Brasch NE, Hamza MS, van Eldik R.

Institute for Inorganic Chemistry, University of Erlangen-Nürnberg,

Egerlandstrasse 1, 91058 Erlangen, Germany.

The reaction of coenzyme B(12) (adenosylcobalamin) with cyanide has been

reinvestigated in detail using spectroscopic and kinetic techniques. It has

been shown that this reaction proceeds in one kinetically observable step,

contradicting previous findings, with rate-determining attack of the first

cyanide (k = (7.4 +/- 0.1) x 10(-3) M(-1) s(-1), 25.0 degrees C, I = 1.0 M

(NaClO(4))). The activation parameters were found to be DeltaH() = 53.0 +/-

0.6 kJ mol(-1), DeltaS() = -127 +/- 3 J mol(-1) K(-1) and DeltaV() = -10.0

+/- 0.4 cm(3) mol(-1), suggesting an associative displacement mechanism. It

is postulated that attack of the first cyanide occurs at the

beta-(5'-deoxy-5'-adenosyl) site rather than at the

alpha-dimethylbenzimidazole site.

PMID: 11669983 [PubMed - as supplied by publisher]

Inorg Chem. 2001 Oct 8;40(21):5440-7.[] Links

Equilibrium and kinetic studies on the reactions of alkylcobalamins with

cyanide.

Hamza MS, Zou X, Brown KL, van Eldik R.

Institute for Inorganic Chemistry, University of Erlangen-Nürnberg,

Egerlandstrasse 1, 91058 Erlangen, Germany.

Ligand substitution equilibria of different alkylcobalamins (RCbl, R = Me,

CH(2)Br, CH(2)CF(3), CHF(2), CF(3)) with cyanide have been studied. It was

found that CN(-) first substitutes the 5,6-dimethylbenzimidazole (Bzm)

moiety in the alpha-position, followed by substitution of the alkyl group

in the beta-position trans to Bzm. The formation constants K(CN) for the

1:1 cyanide adducts (R(CN)Cbl) were found to be 0.38 +/- 0.03, 0.43 +/-

0.03, and 123 +/- 9 M(-1) for R = Me, CH(2)Br, and CF(3), respectively. In

the case of R = CH(2)CF(3), the 1:1 adduct decomposes in the dark with

CN(-) to give (CN)(2)Cbl. The unfavorable formation constants for R = Me

and CH(2)Br indicate the requirement of very high cyanide concentrations to

produce the 1:1 complex, which cause the kinetics of the displacement of

Bzm to be too fast to follow kinetically. The kinetics of the displacement

of Bzm by CN(-) could be followed for R = CH(2)CF(3) and CF(3) to form

CF(3)CH(2)(CN)Cbl and CF(3)(CN)Cbl, respectively, in the rate-determining

step. Both reactions show saturation kinetics at high cyanide

concentration, and the limiting rate constants are characterized by the

activation parameters: R = CH(2)CF(3), DeltaH = 71 +/- 1 kJ mol(-1), DeltaS

= -25 +/- 4 J K(-1) mol(-1), and DeltaV = +8.9 +/- 1.0 cm(3) mol(-1); R =

CF(3), DeltaH = 77 +/- 3 kJ mol(-1), DeltaS = +44 +/- 11 J K(-1) mol(-1),

and DeltaV = +14.8 +/- 0.8 cm(3) mol(-1), respectively. These parameters

are interpreted in terms of an I(d) and D mechanism for R = CH(2)CF(3) and

CF(3), respectively. The results of the study enable the formulation of a

general mechanism that can account for the substitution behavior of all

investigated alkylcobalamins including coenzyme B(12).

PMID: 11578192 [PubMed - indexed for MEDLIN

http://www.botgard.ucla.edu/html/botanytextbooks/economicbotany/Bloodpoisons/ind\

ex.html

Cyanide (a.k.a. hydrogen cyanide, cyanohydric acid, prussic acid, or bitter

almonds) is a potent metabolic poison present in some food crops and other

plants. Cyanide is a small molecule composed of a carbon and nitrogen atom

joined by a stable triple bond. This poison is best known for its

inhibition of many enzymes that are important in animal metabolism.

[Enzymes are proteins that act as catalysts in chemical reactions.] Cyanide

most notably inhibits cytochrome oxidase, one of a group of enzymes

important in cellular respiration. [Respiration is the process by which

both animals and plants break down glucose in the presence of oxygen to

yield carbon dioxide and water and produce valuable energy to maintain

cellular processes and growth.] Without functioning cytochrome oxidase,

respiration is inhibited. Cyanide binds tightly to the enzyme and

permanently inhibits its functioning.

Cyanide is made as an anti-herbivory compound to discourage plant

consumers. Cyanide most often is attached to other molecules in the form of

cyanogenic glycosides. An example of one such compound is amygdalin (from

stems of cherry, apricot, etc., Prunus spp.). In this form, cyanide is

nontoxic to the plant; only in the breakdown of cyanogenic glycosides,

during animal consumption or digestion, is hydrogen cyanide gas released.

For example, cows feeding on some species of grasses containing cyanogenic

glycosides become ill as they chew on the grass. In this fashion, it is

hypothesized that cyanide in nonlethal doses effectively deters herbivory.

Progressive symptoms of cyanide poisoning include gasping, staggering,

paralysis, convulsions, and coma, and the result can be death. The lethal

dose ranges from 0.5 to 3.5 mg per kilogram of body weight, a substantial

quantity. Victims are treated by pumping the stomach and administering

oxygen. As with other poisons, cyanide can be broken down by proper

processing of the plant for safe consumption (see cassava).

Some cyanide containing plants are listed below.

Plant (relative cyanide level)

cassava (++++)

Prunus spp. (+++)

lima beans (certain ones,+++)

sorghum (++)

linseed (++)

millet (++)

bamboo shoots (++)

sweet potatoes (+)

maize (+)

http://www.brooksidepress.org/Products/OperationalMedicine/DATA/operationalmed/M\

anuals/RedHandbook/005Cyanide.htm

MECHANISM OF TOXICITY

Cyanide salts in solid form or in solution are readily absorbed from the

gastrointestinal tract when ingested. Moreover, the lower the pH in the

stomach, the more hydrogen cyanide is released as gas from ingested salts.

Liquid cyanide and cyanide in solution can be absorbed even through intact

skin, but this route of entry is usually not clinically significant.

Parenteral absorption of liquid cyanide can also occur from wounds. Cyanide

is readily absorbed through the eyes, but the most important route of entry

in a battlefield or terrorist scenario would likely be by inhalation.

Following absorption, cyanide is quickly and widely distributed to all

organs and tissues of the body. Ingestion leads to particularly high levels

in the liver when compared with inhalation exposure, but both routes lead

to high concentrations in plasma and erythrocytes and in the heart, lungs,

and brain.

An example of the ability of cyanide to react with metals in the body is

its reaction with the cobalt in hydroxycobalamin (vitamin B12a) to form

cyanocobalamin (vitamin B12). The reactions of cyanide with metals are

reversible and exhibit concentration-dependent equilibria, but the

reactions of cyanide with sulfur-containing compounds are catalyzed by the

enzyme rhodanese (EC 2.8.I.1) and are essentially one-way and irreversible.

The rate-limiting factor in the rhodanese-mediated reactions is usually the

availability of sulfur donors in the body. These reactions can be

accelerated therapeutically by providing a sulfane such as sodium

thiosulfate. The reaction products, thiocyanates and sulfites, are

significantly less toxic than cyanide itself and are eliminated in the

urine. Cyanide also reacts with carbonyl and sulfhydryl groups (directly or

via 3-MPST and other enzymes). However, the two most important kinds of

reactions from the perspective of understanding the classical mechanism of

action of cyanide and its response to specific antidotal therapy are the

reactions with metals and the enzyme-catalyzed reactions with

sulfur-containing compounds.

Cyanide is eliminated unchanged from the body in breath, sweat, and urine -

as sodium thiocyanate in the urine and as iminothiocarboxyllic acid (ITCA)

from reaction with sulfhydryl groups. High concentrations of cyanide in the

body will also lead to measurable increases in urinary elimination of

cyanocobalamin (vitamin B12).

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