cyanocobalamin

シアノコバラミン

関

vitamin B12

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/06/20 13:40:05」(JST)

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Cyanocobalamin
Identifiers
CAS number	68-19-9 Y
PubChem	16212801
UNII	P6YC3EG204 Y
EC number	200-680-0
DrugBank	DB00115
ChEMBL	CHEMBL1200658 N
ATC code	B03BA01, V09XX01 (57Co) V09XX02 (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 (verify) (what is: Y/N?)
Infobox references

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. The amount of cyanide liberated in this process is so small that its toxicity is negligible.

Chemical properties

Cyanocobalamin is the most famous and widely produced 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 B_12r and B_12s, for reduced and super reduced, respectively.

B_12r and B_12s 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 B_12r and B_12s are stable indefinitely under oxygen-free conditions. B_12r appears orange-brown in solution, while B_12s appears bluish-green under natural daylight, and purple under artificial light.

B_12s 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.

For example, cyanocobalamin can be converted to its analog cobalamins via reduction to B_12s, 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 occure between neopentyl chloride and B_12s, whereas the secondary alkyl halide analogs are too unstable to be isolated. 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 B_12s to give the corresponding stable cobalamin analogs. The products are usually extracted and purified by phenol-methylene chloride extraction or by column chromatography.

Cobalamin analogs prepared by this method include the naturally occurring coenzymes methylcobalamin and cobamamide, and also other cobalamins which do not occur naturally, such as vinylcobalamin, carboxymethylcobalamin and cyclohexylcobalamin. This reaction is currently being experimented with for use as a catalyst for chemical dehalogenation, organic reagent and photosensitized catalyst system.

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 potassium cyanide in the presence of sodium nitrite and heat. Since a number of species of Propionibacterium produce no exotoxins or endotoxins and have been granted GRAS status (generally regarded as safe) by the Food and Drug Administration of the United States, they are currently the preferred bacterial fermentation organisms for vitamin B₁₂ production.

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.

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.

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.

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 secreted 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.

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.

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

• Cobamamide
• Hydroxocobalamin
• Methylcobalamin
• Vitamin B12

References

UpToDate Contents

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• 1. ビタミンB12および葉酸欠乏症の診断および治療 diagnosis and treatment of vitamin b12 and folate deficiency
• 2. ビタミンB12および葉酸欠乏症の病因および臨床症状 etiology and clinical manifestations of vitamin b12 and folate deficiency
• 3. ビタミンB12および葉酸欠乏症の生理学 physiology of vitamin b12 and folate deficiency
• 4. 小児における後天性末梢性ニューロパチーの概要 overview of acquired peripheral neuropathies in children
• 5. 疾患予防におけるビタミン補給 vitamin supplementation in disease prevention

Japanese Journal

• Vitrigel-CPT法：コラーゲンビトリゲル膜チャンバーを用いたヒト角膜上皮‐無細胞性実質様培養モデルによる薬剤透過性試験

• 山口 宏之,竹澤 俊明
• 日本毒性学会学術年会 40.1(0), 150630, 2013
• … [方法]最初に、CVMチャンバー（無細胞性実質）の物質透過性をCyanocobalaminおよびFITC-Dextran(FD)の透過速度を指標として評価した。 …
• NAID 130004676650

• Influences of Maternal B₁₂ and Methionine Intake during Gestation and Lactation on Testicular Development of Offspring in Rats

• , , [他], , , , , ,
• Journal of Nutritional Science and Vitaminology 59(3), 238-242, 2013
• … Dams were fed the B12-deficient diet throughout gestation and lactation, whereas dams in a control group were fed a control diet which contained cyanocobalamin in the B12-deficient diet without methionine. …
• NAID 130003368175

• 火事場で馬鹿力を発揮するビタミンB_<12>化合物 : シアン化合物の解毒剤としてのヒドロキソコバラミン

• 渡邉 文雄
• ビタミン 86(8), 451-452, 2012-08-25
• NAID 110009489789

Related Links

• Cyanocobalamin - Wikipedia, the free encyclopedia

Cyanocobalamin is the most common and widely-produced of the chemical compounds that have vitamin activity as vitamin B12. Vitamin B12 is the "generic descriptor" name for any of such vitamers of vitamin B12. Because the body can ...

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リンク元	「シアノコバラミン」
拡張検索	「cyanocobalamin tannin complex」「cobalt 57-cyanocobalamin」

「シアノコバラミン」

　　[★]

英

cyanocobalamin

同

シアノB12 cyano-B12

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関

ビタミンB12

「cyanocobalamin tannin complex」

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シアノコバラミンタンニン複合剤

「cobalt 57-cyanocobalamin」

　　[★] コバルト57-シアノコバラミン