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{{Short description|Form of vitamin B-12}}
{{Infobox drug
| image = Cyanocobalamin-b12.png
| width =
| alt =
| caption = [[Skeletal formula]]
| image2 = Cyanocobalamin-from-xtal-3D-st-noH.png
| width2 =
| alt2 =
| caption2 = [[Ball-and-stick model|Stick model]] of cyanocobalamin based on the crystal structure


| pronounce = sye AN oh koe BAL a min
| tradename = Cobolin-M, Depo-Cobolin, others
| Drugs.com = {{drugs.com|ppa|cyanocobalamin}}
| MedlinePlus = a604029
| DailyMedID = Cyanocobalamin
| pregnancy_AU=
| pregnancy_AU_comment = Exempt
| pregnancy_category=
| routes_of_administration = [[By mouth]], [[intramuscular]], [[nasal spray]]
| class =
| ATCvet =
| ATC_prefix = B03
| ATC_suffix = BA01
| ATC_supplemental =


| legal_AU = 
| legal_AU_comment =
| legal_BR = 
| legal_BR_comment =
| legal_CA = 
| legal_CA_comment =
| legal_DE = 
| legal_DE_comment =
| legal_NZ = 
| legal_NZ_comment =
| legal_UK = 
| legal_UK_comment =
| legal_US = OTC
| legal_US_comment = / Rx-only
| legal_UN = 
| legal_UN_comment =
| legal_status = 


| bioavailability =
| protein_bound =
| metabolism =
| metabolites =
| onset =
| elimination_half-life =
| duration_of_action =
| excretion =


| CAS_number = 68-19-9
| CAS_supplemental =
| PubChem = 16212801
| PubChemSubstance =
| IUPHAR_ligand =
| DrugBank = DB00115
| ChemSpiderID = 24921423
| UNII = P6YC3EG204
| KEGG = D00166
| ChEBI =
| ChEMBL = 2110563
| NIAID_ChemDB =
| PDB_ligand =
| synonyms =


| IUPAC_name =
| C=63 | H=88 | Co=1 | N=14 | O=14 | P=1
| SMILES = CC1=CC2=C(C=C1C)N(C=N2)C3C(C(C(O3)CO)OP(=O)([O-])OC(C)CNC(=O)CCC4(C(C5C6(C(C(C(=C(C7=NC(=CC8=NC(=C(C4=N5)C)C(C8(C)C)CCC(=O)N)C(C7(C)CC(=O)N)CCC(=O)N)C)[N-]6)CCC(=O)N)(C)CC(=O)N)C)CC(=O)N)C)O.[C-]#N.[Co+3]
| StdInChI = 1S/C62H90N13O14P.CN.Co/c1-29-20-39-40(21-30(29)2)75(28-70-39)57-52(84)53(41(27-76)87-57)89-90(85,86)88-31(3)26-69-49(83)18-19-59(8)37(22-46(66)80)56-62(11)61(10,25-48(68)82)36(14-17-45(65)79)51(74-62)33(5)55-60(9,24-47(67)81)34(12-15-43(63)77)38(71-55)23-42-58(6,7)35(13-16-44(64)78)50(72-42)32(4)54(59)73-56;1-2;/h20-21,23,28,31,34-37,41,52-53,56-57,76,84H,12-19,22,24-27H2,1-11H3,(H15,63,64,65,66,67,68,69,71,72,73,74,77,78,79,80,81,82,83,85,86);;/q;-1;+3/p-2/t31-,34-,35-,36-,37+,41-,52-,53-,56-,57?,59-,60+,61+,62+;;/m1../s1
| StdInChI_comment =
| StdInChIKey = FDJOLVPMNUYSCM-QJRSUKKJSA-L
| density =
| density_notes =
| melting_point = 300
| melting_high =
| melting_notes = +
| boiling_point = 300
| boiling_notes = +
| solubility = 1/80
| sol_units = g/ml
| specific_rotation =
}}

'''Cyanocobalamin''' is a form of [[Vitamin B12|vitamin {{chem|B|12}}]] used to treat and prevent [[vitamin B12 deficiency|vitamin {{chem|B|12}} deficiency]] except in the presence of cyanide toxicity. The deficiency may occur in [[pernicious anemia]], following [[gastrectomy|surgical removal of the stomach]], with [[fish tapeworm]], or due to [[bowel cancer]]. It is used by mouth, by [[injection into a muscle]], or as a [[nasal spray]].


Cyanocobalamin is generally well tolerated. Minor side effects may include diarrhea, nausea, upset stomach, and itchiness.Serious side effects may include [[anaphylaxis]], and [[low blood potassium]] resulting in [[heart failure]]. Use is not recommended in those who are allergic to [[cobalt]] or have [[Leber's disease]]. No overdosage or toxicity has been reported. It is less preferred than [[hydroxocobalamin]] for treating vitamin {{chem|B|12}} deficiency because it has slightly lower bioavailability. Some study have shown that it has an antihypotensive effect.


Cyanocobalamin was first manufactured in the 1940s. It is available as a [[generic medication]] and [[over the counter]]. In 2021, it was the 110th most commonly prescribed medication in the United States, with more than 5{{nbsp}}million prescriptions.

==Medical use==
Cyanocobalamin is usually prescribed after surgical removal of part or all of the [[stomach]] or [[intestine]] to ensure adequate serum levels of vitamin {{chem|B|12}}. It is also used to treat [[pernicious anemia]], [[Vitamin B12 deficiency|vitamin {{chem|B|12}} deficiency]] (due to low intake from food or inability to absorb due to genetic or other factors), [[thyrotoxicosis]], [[hemorrhage]], [[malignancy]], liver disease and kidney disease. Cyanocobalamin injections are often prescribed to [[gastric bypass]] patients who have had part of their [[small intestine]] bypassed, making it difficult for {{chem|B|12}} to be acquired via food or vitamins. Cyanocobalamin is also used to perform the [[Schilling test]] to check ability to absorb vitamin {{chem|B|12}}.

Cyanocobalamin is also produced in the body (and then excreted via urine) after intravenous [[hydroxycobalamin]] is used to treat [[cyanide poisoning]].

==Side effects==
Possible side effects of cyanocobalamin injection include allergic reactions such as [[hives]], difficult breathing; redness of the face; swelling of the arms, hands, feet, ankles or lower legs; extreme thirst; and [[diarrhea]]. Less-serious side effects may include headache, dizziness, leg pain, [[itching]], or [[rash]].

Treatment of [[megaloblastic anemia]] with concurrent vitamin {{chem|B|12}} deficiency using {{chem|B|12}} vitamers (including cyanocobalamin), creates the possibility of [[hypokalemia]] due to increased [[erythropoiesis]] (red blood cell production) and consequent cellular uptake of [[potassium]] upon anemia resolution. When treated with cyanocobalamin, patients with [[Leber's disease]] may develop serious [[optic atrophy]], possibly leading to blindness.

==Chemistry==
Vitamin {{chem|B|12}} is the "generic descriptor" name for any [[vitamer]]s of vitamin {{chem|B|12}}. Animals, including humans, can convert cyanocobalamin to any one of the active vitamin {{chem|B|12}} compounds.

Cyanocobalamin is one of the most widely manufactured [[vitamer]]s in the vitamin {{chem|B|12}} family (the family of chemicals that function as {{chem|B|12}} when put into the body), because cyanocobalamin is the most air-stable of the {{chem|B|12}} forms. It is the easiest to purify after it is produced by [[bacterial fermentation]]. It can be obtained as dark red crystals or as an amorphous red powder. Cyanocobalamin is [[hygroscopic]] in the [[anhydrous]] form, and sparingly soluble in water (1:80). It is stable to [[autoclaving]] for short periods at {{convert|121|C|F}}. The vitamin {{chem|B|12}} [[coenzymes]] are unstable in light. After consumption the cyanide [[ligand]] is replaced by other groups ([[adenosyl]], [[methyl]]) to produce the biologically active forms. The [[cyanide]] is converted to [[thiocyanate]] and excreted by the kidney.

===Chemical reactions===
[[File:Various reduced forms of Cyanocobalamin.jpg|thumb|Reduced forms of Cyanocobalamin, with a Co(I) (top), Co(II) (middle), and Co(III) (bottom)]]
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 {{chem|B|12r}} and {{chem|B|12s}}, for reduced and super reduced, respectively.

{{chem|B|12r}} and {{chem|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 {{chem|B|12r}} and {{chem|B|12s}} are stable indefinitely under oxygen-free conditions. {{chem|B|12r}} appears orange-brown in solution, while {{chem|B|12s}} appears bluish-green under natural daylight, and purple under artificial light.

{{chem|B|12s}} is one of the most nucleophilic species known in aqueous solution. This property allows the convenient preparation of cobalamin analogs with different [[substituents]], via [[nucleophilic]] attack on [[alkyl halide]]s and vinyl halides.

For example, cyanocobalamin can be converted to its analog cobalamins via reduction to {{chem|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 {{chem|B|12}} coenzyme analogs. For example, no reaction occurs between [[neopentyl]] chloride and {{chem|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 the [[corrin]] ring. The [[trans effect]] 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 {{chem|H|2|O}} or [[hydroxyl]] ions. Various secondary alkyl halides are then readily attacked by the modified {{chem|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 other cobalamins that do not occur naturally, such as vinylcobalamin, carboxymethylcobalamin and cyclohexylcobalamin. This reaction is under review for use as a catalyst for [[chemical dehalogenation]], organic reagent and photosensitized catalyst systems.

==Production==
Cyanocobalamin is commercially prepared by [[bacterial fermentation]]. Fermentation by a variety of [[microorganism]]s yields a mixture of [[methylcobalamin]], [[hydroxocobalamin]] and [[adenosylcobalamin]]. These compounds are converted to cyanocobalamin by addition of [[potassium cyanide]] in the presence of [[sodium nitrite]] and heat. Since multiple species of ''[[Propionibacterium]]'' produce no [[exotoxin]]s or [[endotoxin]]s and have been granted [[GRAS]] status (generally regarded as safe) by the [[United States Food and Drug Administration]], they are the preferred bacterial fermentation organisms for vitamin {{chem|B|12}} production.

Historically, the physiological form was initially thought to be cyanocobalamin. This was because [[hydroxocobalamin]] produced by bacteria was changed to cyanocobalamin during purification in [[activated charcoal]] columns after separation from the bacterial cultures (because [[cyanide]] is naturally present in activated charcoal). Cyanocobalamin is the form in most pharmaceutical preparations because adding cyanide stabilizes the molecule.

The total world production of vitamin B<sub>12</sub>, by four companies (the French Sanofi-Aventis and three Chinese companies) in 2008 was 35 tonnes.

== Metabolism ==
The two bioactive forms of vitamin {{chem|B|12}} are [[methylcobalamin]] in [[cytosol]] and [[adenosylcobalamin]] in [[mitochondria]]. Multivitamins often contain cyanocobalamin, which is presumably converted to bioactive forms in the body. Both methylcobalamin and adenosylcobalamin are commercially available as supplement pills. The [[MMACHC]] gene product catalyzes the decyanation of cyanocobalamin as well as the dealkylation of alkylcobalamins including methylcobalamin and adenosylcobalamin. This function has also been attributed to [[Cyanocobalamin reductase (cyanide-eliminating)|cobalamin reductases]]. The MMACHC gene product and cobalamin reductases enable the interconversion of cyano- and alkylcobalamins.

Cyanocobalamin is added to fortify nutrition, including baby milk powder, breakfast cereals and [[energy drinks]] for humans, also animal feed for poultry, swine and fish. Vitamin {{chem|B|12}} becomes inactive due to [[hydrogen cyanide]] and [[nitric oxide]] in cigarette smoke. Vitamin {{chem|B|12}} also becomes inactive due to [[nitrous oxide]] {{chem|N|2|O}} commonly known as laughing gas, used for [[anaesthesia]] and as a recreational drug. Vitamin {{chem|B|12}} becomes inactive due to microwaving or other forms of heating.

=== In the cytosol ===
[[Methylcobalamin]] and [[5-methyltetrahydrofolate]] are needed by [[methionine synthase]] in the [[methionine]] cycle to transfer a methyl group from [[5-methyltetrahydrofolate]] to [[homocysteine]], thereby generating [[tetrahydrofolate]] (THF) and [[methionine]], which is used to make [[SAMe]]. [[SAMe]] is the universal methyl donor and is used for [[DNA methylation]] and to make [[lipid bilayer|phospholipid]] [[cell membrane|membranes]], [[choline]], [[sphingomyelin]], [[acetylcholine]], and other [[neurotransmitters]].

=== In mitochondria ===
[[File:Odd-chain FA oxydation.png|thumb|upright|Vitamin {{chem|B|12}} [[adenosylcobalamin]] in [[mitochondrion]]—cholesterol and protein metabolism]]

The enzymes that use {{chem|B|12}} as a built-in cofactor are [[methylmalonyl-CoA mutase]] ([[Protein Data Bank|PDB]] 4REQ) and [[methionine synthase]] ([[Protein Data Bank|PDB]] 1Q8J).

The metabolism of [[propionyl-CoA]] occurs in the mitochondria and requires Vitamin {{chem|B|12}} (as [[adenosylcobalamin]]) to make [[succinyl-CoA]]. When the conversion of propionyl-CoA to succinyl-CoA in the mitochondria fails due to Vitamin {{chem|B|12}} deficiency, elevated blood levels of [[methylmalonic acid]] (MMA) occur. Thus, elevated blood levels of [[homocysteine]] and MMA may both be indicators of [[vitamin B12 deficiency|vitamin {{chem|B|12}} deficiency]].

[[Adenosylcobalamin]] is needed as [[cofactor (biochemistry)|cofactor]] in [[methylmalonyl-CoA mutase]]—MUT enzyme. Processing of cholesterol and protein gives [[propionyl-CoA]] that is converted to [[methylmalonyl-CoA]], which is used by [[methylmalonyl-CoA mutase|MUT enzyme]] to make [[succinyl-CoA]]. Vitamin {{chem|B|12}} is needed to prevent anemia, since making [[porphyrin]] and [[heme]] in [[mitochondria]] for producing hemoglobin in red blood cells depends on [[succinyl-CoA]] made by vitamin {{chem|B|12}}.

=== Absorption and transport ===
Inadequate absorption of vitamin {{chem|B|12}} may be related to [[coeliac disease]]. Intestinal absorption of vitamin {{chem|B|12}} requires successively three different protein molecules: [[haptocorrin]], [[intrinsic factor]] and [[transcobalamin II]].

== See also ==
* [[Methylcobalamin]]
* [[Hydroxocobalamin]]
* [[Adenosylcobalamin]]
* [[Cobalamin biosynthesis]]

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{{二次利用|date=7 March 2024}}
[[Category:B vitamins]]
[[Category:Organocobalt compounds]]
[[Category:Cofactors]]
[[Category:Vitamin B12]]
[[Category:Corrinoids]]
[[Category:Wikipedia medicine articles ready to translate]]

Cyanocobalamin/en - Revision history

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