cyanocobalamin

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 (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}}.{{R|umm}}

Cyanocobalamin is also produced in the body (and then excreted via urine) after intravenous hydroxycobalamin is used to treat cyanide poisoning.{{cite journal | vauthors = MacLennan L, Moiemen N | title = Management of cyanide toxicity in patients with burns | journal = Burns | volume = 41 | issue = 1 | pages = 18–24 | date = February 2015 | pmid = 24994676 | doi = 10.1016/j.burns.2014.06.001 }}

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.{{R|Sides2}}

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.{{R|Anemia}} When treated with cyanocobalamin, patients with Leber's disease may develop serious optic atrophy, possibly leading to blindness.{{R|blind}}

Vitamin {{chem|B|12}} is the "generic descriptor" name for any vitamers of vitamin {{chem|B|12}}. Animals, including humans, can convert cyanocobalamin to any one of the active vitamin {{chem|B|12}} compounds.{{R|PMC2809139}}

Cyanocobalamin is one of the most widely manufactured vitamers 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.{{cite web |title=Cyanocobalamin Injection |url=https://www.empowerpharmacy.com/drugs/cyanocobalamin-vitamin-b12-injection |website=Empower Pharmacy |access-date=2 April 2021}} It is the easiest{{cite web |title=Vitamin B12 (Cyanocobalamin) |url=https://med.libretexts.org/Courses/American_River_College/General_Nutrition_Textbook_(not_Plant-Based)-_reference_for_NUTRI_303_(Hagenburger)/7%3A_Vitamins/7.3%3A_Water_Soluble_Vitamins/Vitamin_B12_(Cyanocobalamin) |website=+Medicine LibreTexts |date=12 May 2017 |access-date=2 April 2021}} to crystallize and therefore easiest{{cite web |title=TERMIUM Plus® |url=https://www.btb.termiumplus.gc.ca/tpv2alpha/alpha-eng.html?lang=eng&i=&index=enw&srchtxt=CYANOCOBALAMIN |website=Canada.ca |date = 8 October 2009|publisher=Government of Canada |access-date=2 April 2021}} 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).{{cite web |title=Nascobal® (Cyanocobalamin, USP) Nasal Spray 500 mcg/spray 0.125 mL Rx only |url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021642s020lbl.pdf |website=Access Data FDA |access-date=2 April 2021}} 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.{{cite book | vauthors = Pimenta E, Calhoun DA, Oparil S | chapter = Chapter 28: Hypertensive emergencies | veditors = Jeremias A, Brown DL |title=Cardiac Intensive Care |date=2010 |publisher=Saunders/Elsevier |location=Philadelphia, PA |isbn=978-1-4160-3773-6 |edition=2nd }}

File:Various reduced forms of Cyanocobalamin.jpg

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.{{R|MechB12}}

{{chem|B|12s}} is one of the most nucleophilic species known in aqueous solution.{{R|MechB12}} This property allows the convenient preparation of cobalamin analogs with different substituents, via nucleophilic attack on alkyl halides and vinyl halides.{{R|MechB12}}

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.{{R|MechB12}} 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.{{R|InnoCatalyst}} The products are usually extracted and purified by phenol-methylene chloride extraction or by column chromatography.{{R|MechB12}}

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.{{R|MechB12}} This reaction is under review for use as a catalyst for chemical dehalogenation, organic reagent and photosensitized catalyst systems.{{R|Catalysis}}

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 {{chem|B|12}} production.{{R|Riaz}}

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).{{cite journal | vauthors = Linnell JC, Matthews DM | title = Cobalamin metabolism and its clinical aspects | journal = Clinical Science | volume = 66 | issue = 2 | pages = 113–121 | date = February 1984 | pmid = 6420106 | doi = 10.1042/cs0660113 }} Cyanocobalamin is the form in most pharmaceutical preparations because adding cyanide stabilizes the molecule.{{R|herbert}}

The total world production of vitamin B₁₂, by four companies (the French Sanofi-Aventis and three Chinese companies) in 2008 was 35 tonnes.{{cite news| vauthors = Zhang Y |date=26 January 2009|url=http://www.highbeam.com/doc/1G1-192899762.html |archive-url=https://web.archive.org/web/20130513111828/http://www.highbeam.com/doc/1G1-192899762.html|url-status=dead|archive-date=13 May 2013|title=New round of price slashing in vitamin B₁₂ sector (Fine and Specialty)|website=China Chemical Reporter}}

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{{Citation needed|date=March 2025|reason=Why do we presume?}}. 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.{{R|Hannibal}} This function has also been attributed to cobalamin reductases.{{R|Watanabe}} The MMACHC gene product and cobalamin reductases enable the interconversion of cyano- and alkylcobalamins.{{R|Quadros}}

Cyanocobalamin is added as an ingredient to fortify{{R|DSM-fortify}} nutrition in products such as baby formula, breakfast cereals and energy drinks as well as livestock feed. Vitamin {{chem|B|12}} becomes inactive when exposed to hydrogen cyanide and nitric oxide in cigarette smoke. Vitamin {{chem|B|12}} deficiency can develop with heavy regular use of nitrous oxide {{chem|N|2|O}}, also known as "laughing gas", used for anaesthesia in a clinical setting or as a propellant gas, it's commonly abused as a recreational drug.{{cite journal | vauthors = Thompson AG, Leite MI, Lunn MP, Bennett DL | title = Whippits, nitrous oxide and the dangers of legal highs | journal = Practical Neurology | volume = 15 | issue = 3 | pages = 207–209 | date = June 2015 | pmid = 25977272 | pmc = 4453489 | doi = 10.1136/practneurol-2014-001071 }} Vitamin {{chem|B|12}} additionally becomes inactive when exposed to intense heat or electromagnetic radiation.{{R|Watanabe2}}

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.

File:Odd-chain FA oxydation.png in mitochondrion—cholesterol and protein metabolism]]

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

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 {{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
• Adenosylcobalamin
• Cobalamin biosynthesis

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{{reflist|refs=

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[https://web.archive.org/web/20070514204818/http://www.umm.edu/altmed/drugs/cyanocobalamin-033700.htm Cyanocobalamin]. University of Maryland Medical Center

{{cite web|title=Cyanocobalamin Injection|url=https://www.nlm.nih.gov/medlineplus/druginfo/meds/a605007.html|website=MedlinePlus|access-date=4 July 2015|archive-url=https://web.archive.org/web/20150419093329/https://www.nlm.nih.gov/medlineplus/druginfo/meds/a605007.html|archive-date=19 April 2015}}

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