Cyanocobalamin: Difference between revisions

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{{Short description|Form of vitamin B-12}}
{{Short description|Form of vitamin B-12}}
{{Infobox drug
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| caption2          = [[Ball-and-stick model|Stick model]] of cyanocobalamin based on the crystal structure
| caption2          = [[Ball-and-stick model|Stick model]] of cyanocobalamin based on the crystal structure


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| pronounce        = sye AN oh koe BAL a min
| pronounce        = sye AN oh koe BAL a min
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| legal_status      = <!--For countries not listed above-->


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| CAS_number        = 68-19-9
| CAS_number        = 68-19-9
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| synonyms          =


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'''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 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]].


<!--T:7-->
<!-- Side effects and mechanism -->
<!-- Side effects and mechanism -->
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 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.


<!--T:8-->
<!-- Society and culture -->
<!-- Society and culture -->
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.
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==
==Medical use== <!--T:9-->
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 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}}.


<!--T:10-->
Cyanocobalamin is also produced in the body (and then excreted via urine) after intravenous [[hydroxycobalamin]] is used to treat [[cyanide poisoning]].
Cyanocobalamin is also produced in the body (and then excreted via urine) after intravenous [[hydroxycobalamin]] is used to treat [[cyanide poisoning]].


==Side effects==
==Side effects== <!--T:11-->
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]].
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]].


<!--T:12-->
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.
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==
==Chemistry== <!--T:13-->
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.
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.


<!--T:14-->
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.
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===
===Chemical reactions=== <!--T:15-->
[[File:Various reduced forms of Cyanocobalamin.jpg|thumb|Reduced forms of Cyanocobalamin, with a Co(I) (top), Co(II) (middle), and Co(III) (bottom)]]
[[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.
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.


<!--T:16-->
{{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|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.


<!--T:17-->
{{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.
{{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.


<!--T:18-->
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.
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.


<!--T:19-->
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.
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==
==Production== <!--T:20-->
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.
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.


<!--T:21-->
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.
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.


<!--T:22-->
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.
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 ==
== Metabolism == <!--T:23-->
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.
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.


<!--T:24-->
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.
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 ===
=== In the cytosol === <!--T:25-->
[[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]].
[[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 ===
=== In mitochondria === <!--T:26-->
[[File:Odd-chain FA oxydation.png|thumb|upright|Vitamin {{chem|B|12}} [[adenosylcobalamin]] in [[mitochondrion]]—cholesterol and protein metabolism]]
[[File:Odd-chain FA oxydation.png|thumb|upright|Vitamin {{chem|B|12}} [[adenosylcobalamin]] in [[mitochondrion]]—cholesterol and protein metabolism]]


<!--T:27-->
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 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).


<!--T:28-->
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]].
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]].


<!--T:29-->
[[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}}.
[[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 ===
=== Absorption and transport === <!--T:30-->
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]].
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 ==
== See also == <!--T:31-->
* [[Methylcobalamin]]
* [[Methylcobalamin]]
* [[Hydroxocobalamin]]
* [[Hydroxocobalamin]]
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* [[Cobalamin biosynthesis]]
* [[Cobalamin biosynthesis]]


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{{二次利用|date=7 March 2024}}
{{二次利用|date=7 March 2024}}
[[Category:B vitamins]]
[[Category:B vitamins]]

Latest revision as of 22:09, 6 April 2024

Other languages:
Cyanocobalamin
Skeletal formula
Stick model of cyanocobalamin based on the crystal structure
Clinical data
Pronunciationsye AN oh koe BAL a min
Trade namesCobolin-M, Depo-Cobolin, others
AHFS/Drugs.comProfessional Drug Facts
MedlinePlusa604029
License data
Pregnancy
category
  • AU: Exempt
Routes of
administration		By mouth, intramuscular, nasal spray
ATC code
Legal status
Legal status
  • US: OTC / Rx-only
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC63H88CoN14O14P
Molar mass1355.388 g·mol−1
3D model (JSmol)
Melting point300 °C (572 °F) +
Boiling point300 °C (572 °F) +
Solubility in water1/80g/ml

Cyanocobalamin is a form of vitamin B
12 used to treat and prevent vitamin B
12 deficiency except in the presence of cyanide toxicity. The deficiency may occur in pernicious anemia, following 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 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 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 B
12. It is also used to treat pernicious anemia, vitamin 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 B
12 to be acquired via food or vitamins. Cyanocobalamin is also used to perform the Schilling test to check ability to absorb vitamin 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 B
12 deficiency using 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 B
12 is the "generic descriptor" name for any vitamers of vitamin B
12. Animals, including humans, can convert cyanocobalamin to any one of the active vitamin B
12 compounds.

Cyanocobalamin is one of the most widely manufactured vitamers in the vitamin B
12 family (the family of chemicals that function as B
12 when put into the body), because cyanocobalamin is the most air-stable of the 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 121 °C (250 °F). The vitamin 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

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 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. 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 B
12 coenzyme analogs. For example, no reaction occurs 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 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 H
2O 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 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 microorganisms 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 exotoxins or endotoxins 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 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 B12, by four companies (the French Sanofi-Aventis and three Chinese companies) in 2008 was 35 tonnes.

Metabolism

The two bioactive forms of vitamin 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 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 B
12 becomes inactive due to hydrogen cyanide and nitric oxide in cigarette smoke. Vitamin B
12 also becomes inactive due to nitrous oxide N
2O commonly known as laughing gas, used for anaesthesia and as a recreational drug. Vitamin 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 phospholipid membranes, choline, sphingomyelin, acetylcholine, and other neurotransmitters.

In mitochondria

Vitamin B
12 adenosylcobalamin in mitochondrion—cholesterol and protein metabolism

The enzymes that use B
12 as a built-in cofactor are methylmalonyl-CoA mutase (PDB 4REQ) and methionine synthase (PDB 1Q8J).

The metabolism of propionyl-CoA occurs in the mitochondria and requires Vitamin B
12 (as adenosylcobalamin) to make succinyl-CoA. When the conversion of propionyl-CoA to succinyl-CoA in the mitochondria fails due to Vitamin 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 B
12 deficiency.

Adenosylcobalamin is needed as 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 MUT enzyme to make succinyl-CoA. Vitamin 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 B
12.

Absorption and transport

Inadequate absorption of vitamin B
12 may be related to coeliac disease. Intestinal absorption of vitamin B
12 requires successively three different protein molecules: haptocorrin, intrinsic factor and transcobalamin II.

See also



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