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Cyanocobalamin

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Cyanocobalamin

Cyanocobalamin
Identifiers
CAS number  YesY
PubChem
UNII  YesY
EC number
DrugBank
ChEMBL  N
ATC code B03,
V09 (57Co)
V09 (58Co)
Properties
Molecular formula C63H88CoN14O14P
Molar mass 1355.38 g/mol
Appearance Dark red solid
Melting point > 300 °C
Boiling point > 300 °C
Solubility in water Soluble
Hazards
MSDS External MSDS from Fisher Scientific
EU classification Not available
S-phrases S24/25
NFPA 704
1
1
Flash point N/A
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
 N   YesY/N?)

Cyanocobalamin is the most common and widely produced form of the chemical compounds that have vitamin B12 activity. Vitamin B12 is the "generic descriptor" name for any of such vitamers of vitamin B12. Because the body can convert cyanocobalamin to any one of the active vitamin B12 compounds, by definition this makes cyanocobalamin itself a form (or vitamer) of B12, albeit a largely artificial one.

Cyanocobalamin usually does not occur in living organisms, but animals can convert commercially produced cyanocobalamin into active (cofactor) forms of the vitamin, such as methylcobalamin.[1]

Chemical properties

Cyanocobalamin is the most famous and widely manufactured vitamer in the vitamin B12 family (the family of chemicals that function as B12 when put into the body), because cyanocobalamin is the most air-stable of the B12 forms. It is the easiest to crystallize and, therefore, easiest to purify after it is produced by bacterial fermentation, or synthesized in vitro. It can be obtained as dark red crystals or as an amorphous red powder. Cyanocobalamin is very hygroscopic in the anhydrous form, and sparingly soluble in water (1:80). It is stable to autoclaving for short periods at 121 °C. The vitamin B12 coenzymes are very unstable in light.

In animals the cyanide ligand is replaced by other groups (adenosyl, methyl), which are the biologically active forms. The remaining portion of the cyanocobalamin remains unchanged.

Chemical reactions

In the cobalamins, cobalt normally exists in the trivalent state, Co(III). However, under reducing conditions, the cobalt center is reduced to Co(II) or even Co(I), which are usually denoted as B12r and B12s, for reduced and super reduced, respectively.

B12r and B12s can be prepared from cyanocobalamin by controlled potential reduction, or chemical reduction using sodium borohydride in alkaline solution, zinc in acetic acid, or by the action of thiols. Both B12r and B12s are stable indefinitely under oxygen-free conditions. B12r appears orange-brown in solution, while B12s appears bluish-green under natural daylight, and purple under artificial light.[2]

B12s is one of the most nucleophilic species known in aqueous solution. It is often referred to as a "supernucleophile". This property allows the convenient preparation of cobalamin analogs with different substituents, via nucleophilic attack on alkyl halides and vinyl halides.[2]

For example, cyanocobalamin can be converted to its analog cobalamins via reduction to B12s, followed by the addition of the corresponding alkyl halides, acyl halides, alkene or alkyne. Steric hindrance is the major limiting factor in the synthesis of the B12 coenzyme analogs. For example, no reaction occurs between neopentyl chloride and B12s, whereas the secondary alkyl halide analogs are too unstable to be isolated.[2] This effect may be due to the strong coordination between benzimidazole and the central cobalt atom, pulling it down into the plane of corrin ring. The trans effect also determines the polarizability of the Co-C bond so formed. However, once the benzimidazole is detached from cobalt by quaternization with methyl iodide, it is replaced by H2O or hydroxyl ions. Various secondary alkyl halides are then readily attacked by the modified B12s to give the corresponding stable cobalamin analogs.[3] The products are usually extracted and purified by phenol-methylene chloride extraction or by column chromatography.[2]

Cobalamin analogs prepared by this method include the naturally occurring coenzymes [4]

Reduced forms of Cyanocobalamin, with a Co(I) (upper) center, Co(II) (middle) center, and Co(III) (lower) center

Production

Cyanocobalamin is commercially prepared by bacterial fermentation. Fermentation by a variety of microorganisms yields a mixture of methyl-, hydroxo-, and adenosylcobalamin. These compounds are converted to cyanocobalamin by addition of [5]

Historically, a form of vitamin B12 called hydroxocobalamin is often produced by bacteria, and was then changed to cyanocobalamin in the process of being purified in activated charcoal columns after being separated from the bacterial cultures. This change was not immediately realized when vitamin B12 was first being extracted for characterization. Cyanide is naturally present in activated charcoal, and hydroxocobalamin, which has great affinity for cyanide, picks it up, and is changed to cyanocobalamin. Cyanocobalamin is the form in most pharmaceutical preparations because adding cyanide stabilizes the molecule.[1]

France accounts for 80% of world production, and more than 10 tonnes/year of this compound is sold; 55% of sales is destined for animal feed, while the remaining 45% is for human consumption.[6]

Pharmaceutical use

Cyanocobalamin is usually prescribed after surgical removal of part or all of the stomach or intestine to ensure adequate levels of vitamin B12 in the bloodstream. It also is used to treat pernicious anemia, vitamin B12 deficiency (due to low intake from food), thyrotoxicosis, hemorrhage, malignancy, liver disease and kidney disease. Cyanocobalamin injections are often prescribed to gastric bypass patients having had part of their small intestine bypassed, making it difficult for B12 to be absorbed via food or vitamins. Cyanocobamide is also used to perform the Schilling test to check a person's ability to absorb vitamin B12.[7]

End product of cyanide poisoning treatment

In cases of cyanide poisoning the patient is given hydroxocobalamin, which is a precursor to cyanocobalamin. The hydroxocobalamin binds with the cyanide ion and forms cyanocobalamin, which can then be excreted by the kidneys. This has been used for many years in France and was approved by the U.S. FDA in Dec 2006, marked under the name Cyanokit.[8][9]

Possible side effects

The oral use of cyanocobalamin may lead to several allergic reactions such as hives; difficult breathing; swelling of the face, lips, tongue, or throat. Less-serious side effects may include headache, nausea, stomach upset, diarrhea, joint pain, itching, or rash.[10]

In the treatment of some forms of anemia (e.g., megaloblastic anemia), the use of cyanocobalamin can lead to severe hypokalemia, sometimes fatal, due to intracellular potassium shift upon anemia resolution (but this same effect should be observed with any B12 vitamer, not just cyanocobalamin). When treated with vitamin B12, patients with Leber's disease may suffer rapid optic atrophy.

Forms of vitamin B12 for injection (such as hydroxocobalamin itself) are commonly available as pharmaceuticals, and are actually the most commonly used injectable forms of vitamin B12 in many countries. Injectable cyanocobalamin remains the most commonly injectable vitamin B12 in the United States.

See also

References

  1. ^ a b Victor Herbert (1988). "Vitamin B-12: plant sources, requirements, and assay". American Journal of Clinical Nutrition 48 (3 Suppl): 852–8.  
  2. ^ a b c d e David Dophin. Preparation of the Reduced Forms of Vitamin B12 and of Some Analogs of the Vitamin B12 Coenzyme Containing a Cobalt-Carbon Bond. D.B. McCormick and L.D. Wright, Eds. 1971;Vol. XVIII:34-54.
  3. ^ [1], On the Mechanism of catalysis by Vitamin B12, by Jonothan D. Brodie.
  4. ^ [2], Environmental-friendly catalysts learned from Vitamin B12-dependent enzymes, by Hisashi Shimakoshi, Yoshio Hisaeda.
  5. ^ Riaz, Muhammad; Fouzia Iqbal and Muhammad Akram (2007). "Microbial production of vitamin B12 by methanol utilizing strain of Pseudomonas specie". Pak J. Biochem. Mol. Biol. 1 40: 5–10. 
  6. ^ Bruno Kaesler (2005), "Vitamins: 9. Vitamin B12 (Cyanocobalamins)",  
  7. ^ http://www.umm.edu/altmed/drugs/cyanocobalamin-033700.htm
  8. ^ Bledsoe, Bryan (2009). Paramedic Care: Principles & Practice, Medical Emergencies. Upper Saddle River, New Jersey: Pearson Education, Inc. p. 471.  
  9. ^ Hamel Jillian "A review of acute cyanide poisoning with a treatment update Critical Care Nurse 2011, 31(1), p. 72-81. doi:10.4037/ccn2011799
  10. ^ "cyanocobalamin (oral)". Cerner Multum, Inc. (Healthwise). 2009-04-21. 
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