Cyanocobalamin: Difference between revisions

{{Short description|Form of vitamin B-12}}

{{Infobox drug

| caption2          = [[Ball-and-stick model|Stick model]] of cyanocobalamin based on the crystal structure

<!-- Clinical data -->

| pronounce        = sye AN oh koe BAL a min

| ATC_supplemental  =

<!-- Legal status -->

| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->

| legal_status      = <!--For countries not listed above-->

<!-- Pharmacokinetic data -->

| bioavailability  =  

| excretion        =

<!-- Identifiers -->

| CAS_number        = 68-19-9

| synonyms          =

<!-- Chemical and physical data -->

| IUPAC_name        =  

'''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]].

<!-- 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.

<!-- 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 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]].

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.

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.

[[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.

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 B₁₂, by four companies (the French Sanofi-Aventis and three Chinese companies) in 2008 was 35 tonnes.

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.

[[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]].

[[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}}.

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]].

* [[Methylcobalamin]]

* [[Hydroxocobalamin]]

* [[Cobalamin biosynthesis]]

{{-}}

{{ATC navboxes|A11|B03}}

{{Tetrapyrroles}}

{{Portal bar | Medicine}}

{{二次利用|date=7 March 2024}}

[[Category:B vitamins]]

[[Category:Corrinoids]]

[[Category:Wikipedia medicine articles ready to translate]]