Biology:Cyanocobalamin

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Short description: Form of vitamin B-12
Cyanocobalamin
Cyanocobalamin-b12.png
Cyanocobalamin-from-xtal-3D-st-noH.png
Stick model of cyanocobalamin based on the crystal structure[1]
Clinical data
Pronunciationsye AN oh koe BAL a min[2]
Trade namesCobolin-M,[2] Depo-Cobolin,[2] others[3]
AHFS/Drugs.comProfessional Drug Facts
MedlinePlusa604029
License data
Pregnancy
category
Routes of
administration		By mouth, intramuscular, nasal spray[5][6]
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 B12 used to treat and prevent vitamin B12 deficiency except in the presence of cyanide toxicity.[7][8][2] The deficiency may occur in pernicious anemia, following surgical removal of the stomach, with fish tapeworm, or due to bowel cancer.[9] [5] It is used by mouth, by injection into a muscle, or as a nasal spray.[5][6]

Cyanocobalamin is generally well tolerated.[10] Minor side effects may include diarrhea, nausea, upset stomach, and itchiness.[11] Serious side effects may include anaphylaxis, and low blood potassium resulting in heart failure.[11] Use is not recommended in those who are allergic to cobalt or have Leber's disease.[9] No overdosage or toxicity has been reported.[11] It is less preferred than hydroxocobalamin for treating vitamin B12 deficiency because it has slightly lower bioavailability. Some study have shown that it has an antihypotensive effect.[5] Vitamin B12 is an essential nutrient meaning that it cannot be made by the body but is required for life.[12][10]

Cyanocobalamin was first manufactured in the 1940s.[13] It is available as a generic medication and over the counter.[5][10] In 2020, it was the 105th most commonly prescribed medication in the United States, with more than 6 million prescriptions.[14][15]

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 B12. 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 B12 to be acquired via food or vitamins. Cyanocobalamin is also used to perform the Schilling test to check ability to absorb vitamin B12.[16]

Cyanocobalamin is also produced in the body (and then excreted via urine) after intravenous hydroxycobalamin is used to treat cyanide poisoning.[17]

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.[18]

Treatment of megaloblastic anemia with concurrent vitamin B12 deficiency using B12 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.[19] When treated with cyanocobalamin, patients with Leber's disease may develop serious optic atrophy, possibly leading to blindness.[20]

Chemistry

Vitamin B12 is the "generic descriptor" name for any vitamers of vitamin B12. Animals, including humans, can convert cyanocobalamin to any one of the active vitamin B12 compounds.[21]

Cyanocobalamin is one of the most widely manufactured vitamers in the vitamin B12 family (the family of chemicals that function as B12 when put into the body), because cyanocobalamin is the most air-stable of the B12 forms.[22] It is the easiest[23] to crystallize and therefore easiest[24] 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).[25] It is stable to autoclaving for short periods at 121 °C (250 °F). The vitamin B12 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.[26]

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 B12r and B12s, for reduced and super reduced, respectively.

B12r and B12s 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 B12r and B12s are stable indefinitely under oxygen-free conditions. B12r appears orange-brown in solution, while B12s appears bluish-green under natural daylight, and purple under artificial light.[27]

B12s is one of the most nucleophilic species known in aqueous solution.[27] This property allows the convenient preparation of cobalamin analogs with different substituents, via nucleophilic attack on alkyl halides and vinyl halides.[27]

For example, cyanocobalamin can be converted to its analog cobalamins via reduction to B12s, 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 B12 coenzyme analogs. For example, no reaction occurs between neopentyl chloride and B12s, whereas the secondary alkyl halide analogs are too unstable to be isolated.[27] 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 H2O or hydroxyl ions. Various secondary alkyl halides are then readily attacked by the modified B12s to give the corresponding stable cobalamin analogs.[28] The products are usually extracted and purified by phenol-methylene chloride extraction or by column chromatography.[27]

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.[27] This reaction is under review for use as a catalyst for chemical dehalogenation, organic reagent and photosensitized catalyst systems.[29]

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 B12 production.[30]

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).[31] Cyanocobalamin is the form in most pharmaceutical preparations because adding cyanide stabilizes the molecule.[32]

The total world production of vitamin B12, by four companies (the French Sanofi-Aventis and three Chinese companies) in 2008 was 35 tonnes.[33]

Metabolism

The two bioactive forms of vitamin B12 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.[34] This function has also been attributed to cobalamin reductases.[35] The MMACHC gene product and cobalamin reductases enable the interconversion of cyano- and alkylcobalamins.[36]

Cyanocobalamin is added to fortify[37] nutrition, including baby milk powder, breakfast cereals and energy drinks for humans, also animal feed for poultry, swine and fish. Vitamin B12 becomes inactive due to hydrogen cyanide and nitric oxide in cigarette smoke. Vitamin B12 also becomes inactive due to nitrous oxide N2O commonly known as laughing gas, used for anaesthesia and as a recreational drug.[38] Vitamin B12 becomes inactive due to microwaving or other forms of heating.[39]

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 B12 adenosylcobalamin in mitochondrion—cholesterol and protein metabolism

The enzymes that use B12 as a built-in cofactor are methylmalonyl-CoA mutase (PDB 4REQ[40]) and methionine synthase (PDB 1Q8J).[41]

The metabolism of propionyl-CoA occurs in the mitochondria and requires Vitamin B12 (as adenosylcobalamin) to make succinyl-CoA. When the conversion of propionyl-CoA to succinyl-CoA in the mitochondria fails due to Vitamin B12 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 B12 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 B12.

Absorption and transport

Inadequate absorption of vitamin B12 may be related to coeliac disease. Intestinal absorption of vitamin B12 requires successively three different protein molecules: haptocorrin, intrinsic factor and transcobalamin II.

See also

References

  1. ↑ "Inorganic Cyanide as Protecting Group in the Stereospecific Reconstitution of Vitamin B12 from an Artificial Green Secocorrinoid". Organic Letters 18 (20): 5292–5295. October 2016. doi:10.1021/acs.orglett.6b02611. PMID 27726382. https://edoc.unibas.ch/53916/1/ol-2016-02611f.R1_Proof_hi.pdf. 
  2. ↑ 2.0 2.1 2.2 2.3 "Vitamin B12 Injection: Side Effects, Uses & Dosage". https://www.drugs.com/vitamin-b12.html. 
  3. ↑ "Cyanocobalamin – Drug Usage Statistics, United States, 2006–2016". https://clincalc.com/DrugStats/Drugs/Cyanocobalamin. 
  4. ↑ https://www.tga.gov.au/therapeutic-goods-exempted-pregnancy-categorisation
  5. ↑ 5.0 5.1 5.2 5.3 5.4 British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 993–994. ISBN 9780857113382. 
  6. ↑ 6.0 6.1 "Cyanocobalamin Side Effects in Detail". https://www.drugs.com/sfx/cyanocobalamin-side-effects.html?form=nasal_spray. 
  7. ↑ "Therapeutic misuse of cyanocobalamin". Lancet 2 (8098): 1053–1054. November 1978. doi:10.1016/s0140-6736(78)92379-6. PMID 82069. 
  8. ↑ "Vitamin B-12: plant sources, requirements, and assay". The American Journal of Clinical Nutrition 48 (3 Suppl): 852–858. September 1988. doi:10.1093/ajcn/48.3.852. PMID 3046314. 
  9. ↑ 9.0 9.1 "DailyMed – cyanocobalamin, isopropyl alcohol". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=da925fe7-2051-487f-a9cf-c288249516e7. 
  10. ↑ 10.0 10.1 10.2 Pharmacology and the Nursing Process E-Book. Elsevier Health Sciences. 2019. p. 83. ISBN 9780323550468. https://books.google.com/books?id=hJGCDwAAQBAJ&pg=PA833. 
  11. ↑ 11.0 11.1 11.2 "Cyanocobalamin - FDA prescribing information, side effects and uses". https://www.drugs.com/pro/cyanocobalamin.html. 
  12. ↑ "Cobalamin". Critical Reviews in Clinical Laboratory Sciences 33 (4): 247–356. 1996. doi:10.3109/10408369609081009. PMID 8875026. 
  13. ↑ Nathan and Oski's Hematology and Oncology of Infancy and Childhood E-Book. Elsevier Health Sciences. 2014. p. 309. ISBN 9780323291774. https://books.google.com/books?id=gjWaBQAAQBAJ&pg=PA309. 
  14. ↑ "The Top 300 of 2020". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  15. ↑ "Cyanocobalamin - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/Cyanocobalamin. 
  16. ↑ Cyanocobalamin. University of Maryland Medical Center
  17. ↑ "Management of cyanide toxicity in patients with burns". Burns 41 (1): 18–24. February 2015. doi:10.1016/j.burns.2014.06.001. PMID 24994676. 
  18. ↑ "Cyanocobalamin Injection". https://www.nlm.nih.gov/medlineplus/druginfo/meds/a605007.html. 
  19. ↑ "Clinical Vitamin B12 Deficiency. Managing Patients". https://www.cdc.gov/ncbddd/b12/patients.html. 
  20. ↑ "Vitamin B12". https://www.nlm.nih.gov/medlineplus/druginfo/natural/926.html. 
  21. ↑ "Advances in the understanding of cobalamin assimilation and metabolism". British Journal of Haematology 148 (2): 195–204. January 2010. doi:10.1111/j.1365-2141.2009.07937.x. PMID 19832808. 
  22. ↑ "Cyanocobalamin Injection". https://www.empowerpharmacy.com/drugs/cyanocobalamin-vitamin-b12-injection. 
  23. ↑ "Vitamin B12 (Cyanocobalamin)". 12 May 2017. 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). 
  24. ↑ "TERMIUM Plus®". Government of Canada. 8 October 2009. https://www.btb.termiumplus.gc.ca/tpv2alpha/alpha-eng.html?lang=eng&i=&index=enw&srchtxt=CYANOCOBALAMIN. 
  25. ↑ "Nascobal® (Cyanocobalamin, USP) Nasal Spray 500 mcg/spray 0.125 mL Rx only". https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021642s020lbl.pdf. 
  26. ↑ "Chapter 28: Hypertensive emergencies". Cardiac Intensive Care (2nd ed.). Philadelphia, PA: Saunders/Elsevier. 2010. ISBN 978-1-4160-3773-6. 
  27. ↑ 27.0 27.1 27.2 27.3 27.4 27.5 "[205] Preparation of the reduced forms of vitamin B12 and of some analogs of the vitamin B12 coenzyme containing a cobalt-carbon bond". [205] Preparation of the reduced forms of vitamin B12 and of some analogs of the vitamin B12 coenzyme containing a cobalt-carbon bond.. Methods in Enzymology. 18. Academic Press. January 1971. pp. 34–52. doi:10.1016/S0076-6879(71)18006-8. ISBN 9780121818821. 
  28. ↑ "On the mechanism of catalysis by vitamin B12". Proceedings of the National Academy of Sciences of the United States of America 62 (2): 461–467. February 1969. doi:10.1073/pnas.62.2.461. PMID 5256224. Bibcode: 1969PNAS...62..461B. 
  29. ↑ "Environmental-friendly catalysts learned from Vitamin B12-dependent enzymes". Tcimail 128: 2. http://www.tciamerica.com/tcimail/backnumber/article/138drE.pdf. [yes|permanent dead link|dead link}}]
  30. ↑ "Microbial production of vitamin B12 by methanol utilizing strain of Pseudomonas specie". Pak J. Biochem. Mol. Biol 40: 5–10. 2007. https://pu-pk.academia.edu/MuhammadAkram/Papers/83315/Microbial_production_of_vitamin_B12_by_methanol_utilizing_strain_of. Retrieved 31 October 2017. 
  31. ↑ "Cobalamin metabolism and its clinical aspects". Clinical Science 66 (2): 113–121. February 1984. doi:10.1042/cs0660113. PMID 6420106. 
  32. ↑ "Vitamin B-12: plant sources, requirements, and assay". The American Journal of Clinical Nutrition 48 (3 Suppl): 852–858. September 1988. doi:10.1093/ajcn/48.3.852. PMID 3046314. 
  33. ↑ "New round of price slashing in vitamin B12 sector (Fine and Specialty)". 26 January 2009. http://www.highbeam.com/doc/1G1-192899762.html. 
  34. ↑ "Processing of alkylcobalamins in mammalian cells: A role for the MMACHC (cblC) gene product". Molecular Genetics and Metabolism 97 (4): 260–266. August 2009. doi:10.1016/j.ymgme.2009.04.005. PMID 19447654. 
  35. ↑ "Purification and characterization of aquacobalamin reductases from mammals". Vitamins and Coenzymes Part K. Methods in Enzymology. 281. 1997. pp. 295–305. doi:10.1016/S0076-6879(97)81036-1. ISBN 9780121821821. 
  36. ↑ Quadros, E. V.; Jackson, Beverley; Hoffbrand, A. V.; Linnell, J. C. (2019-10-08) (in en). Interconversion of cobalamins in human lymphocytes in vitro and the influence of nitrous oxide on synthesis of cobalamin coenzymes. De Gruyter. pp. 1045–1054. doi:10.1515/9783111510828-118. ISBN 978-3-11-151082-8. https://www.degruyter.com/document/doi/10.1515/9783111510828-118/html. 
  37. ↑ "DSM in Food, Beverages & Dietary Supplements". DSM. http://www.dsm.com/markets/foodandbeverages/en_US/products/vitamins/vitamin-b12.html. 
  38. ↑ "Whippits, nitrous oxide and the dangers of legal highs". Practical Neurology 15 (3): 207–209. June 2015. doi:10.1136/practneurol-2014-001071. PMID 25977272. 
  39. ↑ "Effects of Microwave Heating on the Loss of Vitamin B(12) in Foods". Journal of Agricultural and Food Chemistry 46 (1): 206–210. January 1998. doi:10.1021/jf970670x. PMID 10554220. 
  40. ↑ "Conformational changes on substrate binding to methylmalonyl CoA mutase and new insights into the free radical mechanism". Structure 6 (6): 711–720. June 1998. doi:10.1016/S0969-2126(98)00073-2. PMID 9655823. 
  41. ↑ "Structures of the N-terminal modules imply large domain motions during catalysis by methionine synthase". Proceedings of the National Academy of Sciences of the United States of America 101 (11): 3729–3736. March 2004. doi:10.1073/pnas.0308082100. PMID 14752199. Bibcode: 2004PNAS..101.3729E. 

pt:Cianocobalamina



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