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 Stick model of cyanocobalamin based on the crystal structure[1] | |
| Clinical data | |
|---|---|
| Pronunciation | sye AN oh koe BAL a min[2] |
| Trade names | Cobolin-M,[2] Depo-Cobolin,[2] others[3] |
| AHFS/Drugs.com | Professional Drug Facts |
| MedlinePlus | a604029 |
| License data | |
| Pregnancy category | |
| Routes of administration | By mouth,intramuscular,nasal spray[5][6] |
| ATC code | |
| Legal status | |
| Legal status | |
| Identifiers | |
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| CAS Number | |
| PubChemCID | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEMBL | |
| ECHA InfoCard | 100.000.618 |
| Chemical and physical data | |
| Formula | C63H88CoN14O14P |
| Molar mass | 1355.388 g·mol−1 |
| 3D model (JSmol) | |
| Melting point | 300 °C (572 °F) + |
| Boiling point | 300 °C (572 °F) + |
| Solubility in water | 1/80g/ml |
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Cyanocobalamin is a form ofvitaminB
12 used to treat and preventvitaminB
12 deficiency except in the presence ofcyanide toxicity.[8][9][2] The deficiency may occur inpernicious anemia, followingsurgical removal of the stomach, withfish tapeworm, or due tobowel cancer.[10][5] It is used by mouth, byinjection into a muscle, or as anasal spray.[5][6]
Cyanocobalamin is generally well tolerated.[11] Minor side effects may include diarrhea, nausea, upset stomach, and itchiness.[12] Serious side effects may includeanaphylaxis, andlow blood potassium resulting inheart failure.[12] Use is not recommended in those who are allergic tocobalt or haveLeber's disease.[10] No overdosage or toxicity has been reported.[12] It is less preferred thanhydroxocobalamin for treating vitaminB
12 deficiency because it has a slightly lowerbioavailability. Some studies have shown it to possess an antihypotensive effect.[5] VitaminB
12 is anessential nutrient meaning that it cannot be made by the body but is required for life.[13][11]
Cyanocobalamin was first manufactured in the 1940s.[14] It is available as ageneric medication andover the counter.[5][11] In 2023, it was the 104th most commonly prescribed medication in the United States, with more than 6 million prescriptions.[15][16]
Cyanocobalamin is usually prescribed after surgical removal of part or all of thestomach orintestine to ensure adequate serum levels of vitaminB
12. It is also used to treatpernicious anemia,vitaminB
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 togastric bypass patients who have had part of theirsmall intestine bypassed, making it difficult forB
12 to be acquired via food or vitamins. Cyanocobalamin is also used to perform theSchilling test to check ability to absorb vitaminB
12.[17]
Cyanocobalamin is also produced in the body (and then excreted via urine) after intravenoushydroxycobalamin is used to treatcyanide poisoning.[18]
Possible side effects of cyanocobalamin injection include allergic reactions such ashives, difficult breathing; redness of the face; swelling of the arms, hands, feet, ankles or lower legs; extreme thirst; anddiarrhea. Less-serious side effects may include headache, dizziness, leg pain,itching, orrash.[19]
Treatment ofmegaloblastic anemia with concurrent vitaminB
12 deficiency usingB
12 vitamers (including cyanocobalamin), creates the possibility ofhypokalemia due to increasederythropoiesis (red blood cell production) and consequent cellular uptake ofpotassium upon anemia resolution.[20] When treated with cyanocobalamin, patients withLeber's disease may develop seriousoptic atrophy, possibly leading to blindness.[21]
VitaminB
12 is the "generic descriptor" name for anyvitamers of vitaminB
12. Animals, including humans, can convert cyanocobalamin to any one of the active vitaminB
12 compounds.[22]
Cyanocobalamin is one of the most widely manufacturedvitamers in the vitaminB
12 family (the family of chemicals that function asB
12 when put into the body), because cyanocobalamin is the most air-stable of theB
12 forms.[23] It is the easiest[24] to crystallize and therefore easiest[25] to purify after it is produced bybacterial fermentation. It can be obtained as dark red crystals or as an amorphous red powder. Cyanocobalamin ishygroscopic in theanhydrous form, and sparingly soluble in water (1:80).[26] It is stable toautoclaving for short periods at 121 °C (250 °F). The vitaminB
12coenzymes are unstable in light. After consumption the cyanideligand is replaced by other groups (adenosyl,methyl) to produce the biologically active forms. Thecyanide is converted tothiocyanate and excreted by the kidney.[27]
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 asB
12r andB
12s, for reduced and super reduced respectively.
B
12r andB
12s can be prepared from cyanocobalamin by controlled potential reduction, or chemical reduction usingsodium borohydride in alkaline solution,zinc inacetic acid, or by the action ofthiols. BothB
12r andB
12s are stable indefinitely under oxygen-free conditions.B
12r appears orange-brown in solution, whileB
12s appears bluish-green under natural daylight, and purple under artificial light.[28]
B
12s is one of the most nucleophilic species known in aqueous solution.[28] This property allows the convenient preparation of cobalamin analogs with differentsubstituents, vianucleophilic attack onalkyl halides and vinyl halides.[28]
For example, cyanocobalamin can be converted to its analog cobalamins via reduction toB
12s, followed by the addition of the correspondingalkyl halides,acyl halides,alkene oralkyne.Steric hindrance is the major limiting factor in the synthesis of theB
12 coenzyme analogs. For example, no reaction occurs betweenneopentyl chloride andB
12s, whereas the secondary alkyl halide analogs are too unstable to be isolated.[28] This effect may be due to the strong coordination betweenbenzimidazole and the central cobalt atom, pulling it down into the plane of thecorrin ring. Thetrans effect determines the polarizability of the Co–C bond so formed. However, once thebenzimidazole is detached from cobalt by quaternization withmethyl iodide, it is replaced byH
2O orhydroxyl ions. Various secondary alkyl halides are then readily attacked by the modifiedB
12s to give the corresponding stable cobalamin analogs.[29] The products are usually extracted and purified by phenol-methylene chloride extraction or by column chromatography.[28]
Cobalamin analogs prepared by this method include the naturally occurring coenzymesmethylcobalamin andcobamamide, and other cobalamins that do not occur naturally, such as vinylcobalamin, carboxymethylcobalamin and cyclohexylcobalamin.[28] This reaction is under review for use as a catalyst forchemical dehalogenation, organic reagent and photosensitized catalyst systems.[30]
Cyanocobalamin is commercially prepared bybacterial fermentation. Fermentation by a variety ofmicroorganisms yields a mixture ofmethylcobalamin,hydroxocobalamin andadenosylcobalamin. These compounds are converted to cyanocobalamin by addition ofpotassium cyanide in the presence ofsodium nitrite and heat. Since multiple species ofPropionibacterium produce noexotoxins orendotoxins and have been grantedGRAS status (generally regarded as safe) by theUnited States Food and Drug Administration, they are the preferred bacterial fermentation organisms for vitaminB
12 production.[31]
Historically, the physiological form was initially thought to be cyanocobalamin. This was becausehydroxocobalamin produced by bacteria was changed to cyanocobalamin during purification inactivated charcoal columns after separation from the bacterial cultures (becausecyanide is naturally present in activated charcoal).[32] Cyanocobalamin is the form in most pharmaceutical preparations because adding cyanide stabilizes the molecule.[33]
The total world production of vitamin B12, by four companies (the French Sanofi-Aventis and three Chinese companies) in 2008 was 35 tonnes.[34]
The two bioactive forms of vitaminB
12 aremethylcobalamin incytosol andadenosylcobalamin inmitochondria. Multivitamins often contain cyanocobalamin, which is presumably converted to bioactive forms in the body[citation needed]. Both methylcobalamin and adenosylcobalamin are commercially available as supplement pills. TheMMACHC gene product catalyzes the decyanation of cyanocobalamin as well as the dealkylation of alkylcobalamins including methylcobalamin and adenosylcobalamin.[35] This function has also been attributed tocobalamin reductases.[36] The MMACHC gene product and cobalamin reductases enable the interconversion of cyano- and alkylcobalamins.[37]
Cyanocobalamin is added as an ingredient to fortify[38] nutrition in products such as baby formula, breakfast cereals andenergy drinks as well as livestock feed. VitaminB
12 becomes inactive when exposed tohydrogen cyanide andnitric oxide in cigarette smoke. VitaminB
12 deficiency can develop with heavy regular use ofnitrous oxideN
2O, also known as "laughing gas", used foranaesthesia in a clinical setting or as a propellant gas, it's commonly abused as a recreational drug.[39] VitaminB
12 additionally becomes inactive when exposed to intense heat or electromagnetic radiation.[40]
Methylcobalamin and5-methyltetrahydrofolate are needed bymethionine synthase in themethionine cycle to transfer a methyl group from5-methyltetrahydrofolate tohomocysteine, thereby generatingtetrahydrofolate (THF) andmethionine, which is used to makeSAMe.SAMe is the universal methyl donor and is used forDNA methylation and to makephospholipidmembranes,choline,sphingomyelin,acetylcholine, and otherneurotransmitters.
The enzymes that useB
12 as a built-in cofactor aremethylmalonyl-CoA mutase (PDB 4REQ[41]) andmethionine synthase (PDB 1Q8J).[42]
The metabolism ofpropionyl-CoA occurs in the mitochondria and requires VitaminB
12 (asadenosylcobalamin) to makesuccinyl-CoA. When the conversion of propionyl-CoA to succinyl-CoA in the mitochondria fails due to VitaminB
12 deficiency, elevated blood levels ofmethylmalonic acid (MMA) occur. Thus, elevated blood levels ofhomocysteine and MMA may both be indicators ofvitaminB
12 deficiency.
Adenosylcobalamin is needed ascofactor inmethylmalonyl-CoA mutase—MUT enzyme. Processing of cholesterol and protein givespropionyl-CoA that is converted tomethylmalonyl-CoA, which is used byMUT enzyme to makesuccinyl-CoA. VitaminB
12 is needed to prevent anemia, since makingporphyrin andheme inmitochondria for producing hemoglobin in red blood cells depends onsuccinyl-CoA made by vitaminB
12.
Inadequate absorption of vitaminB
12 may be related tocoeliac disease. Intestinal absorption of vitaminB
12 requires successively three different protein molecules:haptocorrin,intrinsic factor andtranscobalamin II.
