Cyanocobalamin

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Cyanocobalamin
Systematic (IUPAC) name
?
Identifiers
CAS number	68-19-9
ATC code	B03BB01
PubChem	5479203
DrugBank	APRD00326
Chemical data
Formula	C63H88CoN14O14P
Mol. mass	1355.37 g/mol
Pharmacokinetic data
Bioavailability	readily absorbed in lower half ileum
Protein binding	Very high to specific transcobalamins plasma proteins Binding of hydroxocobalamin is slightly higher than cyanocobalamin.
Metabolism	hepatic
Half life	Approximately 6 days (400 days in the liver)
Excretion	renal
Therapeutic considerations
Pregnancy cat.	?
Legal status	POM(UK)
Routes	oral, iv

Cyanocobalamin is a compound that is metabolized to a vitamin in the B complex commonly known as vitamin B₁₂ (or B₁₂ for short).

The name vitamin B₁₂ is used in two different ways. In a broad sense it refers to a group of cobalt-containing compounds known as cobalamins - cyanocobalamin (an artifact formed as a result of the use of cyanide in the purification procedures), hydroxocobalamin and the two coenzyme forms of B₁₂, methylcobalamin (MeB₁₂) and 5-deoxyadenosylcobalamin (adenosylcobalamin - AdoB₁₂). In a more specific way, the term B₁₂ is used to refer to only one of these forms, cyanocobalamin, which is the principal B₁₂ form used for foods and in nutritional supplements.

Pseudo-B₁₂ refers to B₁₂-like substances which are found in certain organisms; however, these substances do not have B₁₂ biological activity for humans.

Contents 1 Structure 2 Synthesis 3 Functions 4 History as a treatment for anemia 5 Other medical uses 6 Deficiency 6.1 Diagnosis of B12 deficiency 6.2 Treatment of B12 deficiency 7 Sources 8 Allergies 9 Side effects, contraindications, and warnings 10 Pregnancy and breastfeeding 11 Interactions 11.1 Interactions with drugs 11.2 Interactions with herbs and dietary supplements 12 External links

[edit] Structure

B₁₂ is the most chemically complex of all the vitamins. The structure of B₁₂ is based on a corrin ring, which is similar to the porphyrin ring found in heme, chlorophyll, and cytochrome. The central metal ion is Co (cobalt). Four of the six coordination sites are provided by the corrin ring, and a fifth by a dimethylbenzimidazole group. The sixth coordination site, the center of reactivity, is variable, being a cyano group (-CN), a hydroxyl group (-OH), a methyl group (-CH₃) or a 5'-deoxyadenosyl group (here the C5' atom of the deoxyribose forms the covalent bond with Co), respectively, to yield the four B₁₂ forms mentioned above. The covalent C-Co bond is one of first examples of carbon-metal bonds in biology. The hydrogenases and, by necessity, enzymes associated with CO utilization, involve metal-carbon bonds.^[1]

[edit] Synthesis

B₁₂ cannot be made by plants or animals^[2], as the only type of organisms that have the enzymes required for the synthesis of B₁₂ are bacteria and archaea. The total synthesis of B₁₂ was reported by Robert Burns Woodward^[3] and Albert Eschenmoser^[4], and remains one of the classic feats of total synthesis.

[edit] Functions

Coenzyme B₁₂'s reactive C-Co bond participates in two types of enzyme-catalyzed reactions. ^[5]

1. Rearrangements in which a hydrogen atom is directly transferred between two adjacent atoms with concomitant exchange of the second substituent, X, which may be a carbon atom with substituents, an oxygen atom of an alcohol, or an amine.
2. Methyl (-CH₃) group transfers between two molecules.

In humans there are only two coenzyme B₁₂-dependent enzymes:

1. MUT which uses the AdoB₁₂ form and reaction type 1 to catalyze a carbon skeleton rearrangement (the X group is -COSCoA). MUT's reaction converts MMl-CoA to Su-CoA, an important step in the extraction of energy from proteins and fats (for more see MUT's reaction mechanism)
2. MTR, a methyl transfer enzyme, which uses the MeB₁₂ and reaction type 2 to catalyzes the conversion of the amino acid Hcy into Met (for more see MTR's reaction mechanism).

[edit] History as a treatment for anemia

B₁₂ deficiency is the cause of several forms of anemia. The treatment for this disease was first devised by William Murphy who devised experiments on anemia in dogs due to blood loss and then fed them various substances to see what (if anything) would make them healthy again. He discovered that ingesting large amounts of liver seemed to cure the disease. George Minot and George Whipple then set about to chemically isolate the curative substance and ultimately were able to isolate vitamin B₁₂ from the liver. For this, all three shared the 1934 Nobel Prize in Medicine.

The chemical structure of the molecule was determined by Dorothy Crowfoot Hodgkin and her team in 1956, based on crystallographic data.

[edit] Other medical uses

Hydroxycobalamin is used in Europe both for vitamin B₁₂ deficiency and as a treatment for cyanide poisoning, sometimes with a large amount (5-10 g) given intravenously, and sometimes in combination with sodium thiosulfate^[6]. The mechanism of action is straightforward, the hydroxycobalamin hydroxide ligand is displaced by the toxic cyanide ion, and the resulting harmless B₁₂ complex is excreted in urine. In the United States, the FDA has approved in 2006 the use of hydroxocobalamin for acute treatment of cyanide poisoning.

[edit] Deficiency

The usual daily intake in the Western diet is 5-7 µg (Food and Drug Administration (FDA) Daily Value ^[7]); the daily requirement is 1-2 µg. B₁₂ is mostly absorbed in the terminal ileum. The production of intrinsic factor in the parietal cells of the stomach is vital to absorption of this vitamin in terminal ileum. Megaloblastic anemia can result from inadequate intake of B₁₂, inadequate production of intrinsic factor (pernicious anemia), disorders of the terminal ileum resulting in malabsorption, or by competition for available B₁₂ (such as fish tapeworms or bacteria present in blind loop syndrome).

Metformin can also be associated with vitamin B₁₂ deficiency^[8]. Metformin is a common drug-induced cause of B₁₂ deficiency. It is felt that metformin inhibits calcium-dependent ileal absorption of the B₁₂-intrinsic factor complex.

Important limitations of this study include its retrospective design, lack of information about neurologic symptoms, and lack of a confirmatory biochemical test for B₁₂ deficiency such as methylmalonic acid measurements. Nevertheless, the findings emphasize that neurologists should consider the possibility of B₁₂ deficiency in diabetic patients with neurologic symptoms while taking metformin.

B₁₂ deficiency is manifested primarily by anemia and macrocytosis; other cell lines such as white blood cells and platelets are often also low. Bone marrow examination may show megaloblastic hemopoiesis. Serum homocysteine and methylmalonic acid levels are also high in B₁₂ deficiency and can be helpful if the diagnosis is unclear.

Neurological signs of B₁₂ deficiency, which can occur without accompanying hematologic abnormalities, include demyelination and irreversible nerve cell death. Symptoms include numbness or tingling of the extremities and an ataxic gait, a syndrome known as subacute combined degeneration of the cord.

The American Psychiatric Association's American Journal of Psychiatry has published studies showing a relationship between depression levels and deficient B₁₂ blood levels in elderly people in 2000 ^[9] and 2002 ^[10].

[edit] Diagnosis of B₁₂ deficiency

Serum B₁₂ levels are often low in B₁₂ deficiency, but there does not exist a robust assay, and if other features of B₁₂ deficiency are present then the diagnosis must not be discounted. One possible explanation for normal B₁₂ levels in B₁₂ deficiency is antibody interference in people with high titres of intrinsic factor antibody.^[11] Bone marrow aspiration, serum homocysteine and methylmalonic acid levels can also be helpful.^[12]

[edit] Treatment of B₁₂ deficiency

Traditionally, treatment for B₁₂ deficiency was through intramuscular injections of cyanocobalamin. However, it has been appreciated since the 1960s that deficiency can sometimes be treated with oral B₁₂ supplements when given in sufficient doses. When given in oral doses ranging from 0.1–2 mg daily, B₁₂ can be absorbed in a pathway that does not require an intact ileum or intrinsic factor. ^[13][14] Oral absorption is limited so regular intramuscular injections of cyanocobalamin or hydroxocobalamin are necessary to restore systemic stores to physiological levels. The Schilling test can determine whether symptoms of B₁₂ deficiency are caused by lack of intrinsic factor, though this is being performed less often due to the lack of availability of reagent for the test.

[edit] Sources

Vitamin B₁₂ is naturally found in foods that harbor B₁₂ bacteria including meat (especially liver and shellfish), eggs, and milk products. Fortified breakfast cereals are a particularly valuable source of vitamin B₁₂ for vegetarians and vegans. Table 1 lists a variety of food sources of vitamin B₁₂.

B₁₂ can be supplemented in healthy subjects by oral pill; sublingual pill, liquid, or strip; or by injection. B₁₂ is available singly or in combination with other supplements. B₁₂ supplements are available in forms including cyanocobalamin, hydroxocobalamin, methylcobalamin, and adenosylcobalamin (sometimes called cobamamide or dibencozide).

Cyanocobalamin is converted to its active forms, first hydroxocobalamin and then methylcobalamin and adenosylcobalamin in the liver. A 2003 study found no significant difference in absorption for serum levels from oral vs sublingual delivery of 500 micrograms of cobalamin ^[15]. Injection is useful and usually necessary in cases where digestive absorption is impaired. Oral absorption is complex and requires specific intestinal transport proteins (intrinsic factor) produced in the stomach. In any case the absorption is saturated and is rate limited.

While lacto-ovo vegetarians usually get enough B₁₂ through dairy products or eggs, it may be found lacking in those practicing vegan diets who do not use multivitamin supplements or eat B₁₂ fortified foods, such as fortified breakfast cereals, fortified soy-based products, and fortified energy bars. Claimed sources of B₁₂ that have been shown through direct studies^[16] of vegans to be inadequate or unreliable include, nori (a seaweed), barley grass, and human gut bacteria. However B₁₂ deficiencies in vegans are so uncommon that the medical press still record cases. ^[17] People on a vegan raw food diet are also susceptible to B₁₂ deficiency if no supplementation is used^[18].

A natural vegan source of B₁₂ is the Chinese herb Dang Gui (Angelica sinensis) ^[19]. The herb is used in Traditional Chinese medicine for treating anemia.[1] Other potential sources of B₁₂ for vegans include Indonesian tempeh [2], ontjom, and other fermented food products. Spirulina, an algae that has recently gained popularity as a dietary supplement, may also contain some B₁₂. Another source of B₁₂ is yeast spreads, such as Marmite and Vegemite, which are suitable for vegetarians and vegans.

Interestingly, certain insects such as termites have been found to contain B₁₂. ^[20]

Cyanocobalamin may also found in many energy drinks.

[edit] Allergies

Vitamin B₁₂ supplements should be avoided in people sensitive or allergic to cobalamin, cobalt or any other product ingredients.

[edit] Side effects, contraindications, and warnings

• Cardiovascular: Caution should be used in patients undergoing angioplasty since an intravenous loading dose of folic acid, vitamin B6 and vitamin B₁₂ followed by oral administration of folic acid 1.2mg plus vitamin B6 48mg and vitamin B₁₂ 60mcg taken daily after coronary stenting might actually increase restenosis rates. Due to the potential for harm this combination of vitamins should not be recommended for patients receiving coronary stents.
• Dermatologic: Itching, rash, transitory exanthema, and urticaria have been reported. Vitamin B₁₂ (20 micrograms/day) and pyridoxine (80mg/day) has been associated with cases of rosacea fulminans, characterized by intense erythema with nodules, papules, and pustules. Symptoms may persist for up to 4 months after the supplement is stopped, and may require treatment with systemic corticosteroids and topical therapy.

• Gastrointestinal: Diarrhea has been reported.
• Hematologic: Peripheral vascular thrombosis has been reported. Treatment of vitamin B₁₂ deficiency can unmask polycythemia vera, which is characterized by an increase in blood volume and the number of red blood cells. The correction of megaloblastic anemia with vitamin B₁₂ can result in fatal hypokalemia and gout in susceptible individuals, and it can obscure folate deficiency in megaloblastic anemia. Caution is warranted.

• Leber's disease: Vitamin B₁₂ in the form of cyanocobalamin is contraindicated in early Leber's disease, which is hereditary optic nerve atrophy. Vitamin B₁₂ can cause severe and swift optic atrophy.

[edit] Pregnancy and breastfeeding

Vitamin B₁₂ is likely safe when used orally in amounts that do not exceed the recommended dietary allowance (RDA). The RDA for vitamin B₁₂ in pregnant women is 2.6mcg per day and 2.8mcg during lactation periods.

There is insufficient reliable information available about the safety of consuming greater amounts of Vitamin B₁₂ during pregnancy.

[edit] Interactions

[edit] Interactions with drugs

• Alcohol (ethanol): Excessive alcohol intake lasting longer than two weeks can decrease vitamin B₁₂ absorption from the gastrointestinal tract.

• Aminosalicylic acid (para-aminosalicylic acid, PAS, Paser): Aminosalicylic acid can reduce oral vitamin B₁₂ absorption, possibly by as much as 55%, as part of a general malabsorption syndrome. Megaloblastic changes, and occasional cases of symptomatic anemia have occurred, usually after doses of 8 to 12 grams/day for several months. Vitamin B₁₂ levels should be monitored in people taking aminosalicylic acid for more than one month.

• Antibiotics: An increased bacterial load can bind significant amounts of vitamin B₁₂ in the gut, preventing its absorption. In people with bacterial overgrowth of the small bowel, antibiotics such as metronidazole (Flagyl®) can actually improve vitamin B₁₂ status. The effects of most antibiotics on gastrointestinal bacteria are unlikely to have clinically significant effects on vitamin B₁₂ levels.

• Birth control pills: The data regarding the effects of oral contraceptives on vitamin B₁₂ serum levels are conflicting. Some studies have found reduced serum levels in oral contraceptive users, but others have found no effect despite use of oral contraceptives for up to 6 months. When oral contraceptive use is stopped, normalization of vitamin B₁₂ levels usually occurs. Lower vitamin B₁₂ serum levels seen with oral contraceptives probably are not clinically significant.

• Chloramphenicol (Chloromycetin®): Limited case reports suggest that chloramphenicol can delay or interrupt the reticulocyte response to supplemental vitamin B₁₂ in some patients. Blood counts should be monitored closely if this combination cannot be avoided.
• Cobalt irradiation: Cobalt irradiation of the small bowel can decrease gastrointestinal (GI) absorption of vitamin B₁₂.

• Colchicine: Colchicine in doses of 1.9 to 3.9mg/day can disrupt normal intestinal mucosal function, leading to malabsorption of several nutrients, including vitamin B₁₂. Lower doses do not seem to have a significant effect on vitamin B₁₂ absorption after 3 years of colchicine therapy. The significance of this interaction is unclear. Vitamin B₁₂ levels should be monitored in people taking large doses of colchicine for prolonged periods.

• Colestipol (Colestid®), Cholestyramine (Questran®): These resins used for sequestering bile acids in order to decrease cholesterol, can decrease gastrointestinal (GI) absorption of vitamin B₁₂. It is unlikely that this interaction will deplete body stores of vitamin B₁₂ unless there are other factors contributing to deficiency. In a group of children treated with cholestyramine for up to 2.5 years there was not any change in serum vitamin B₁₂ levels. Routine supplements are not necessary.

• H₂-receptor antagonists: include cimetidine (Tagamet®), famotidine (Pepcid®), nizatidine (Axid®), and ranitidine (Zantac®). Reduced secretion of gastric acid and pepsin produced by H₂ blockers can reduce absorption of protein-bound (dietary) vitamin B₁₂, but not of supplemental vitamin B₁₂. Gastric acid is needed to release vitamin B₁₂ from protein for absorption. Clinically significant vitamin B₁₂ deficiency and megaloblastic anemia are unlikely, unless H₂ blocker therapy is prolonged (2 years or more), or the person's diet is poor. It is also more likely if the person is rendered achlorhydric (with complete absence of gastric acid secretion), which occurs more frequently with proton pump inhibitors than H₂ blockers. Vitamin B₁₂ levels should be monitored in people taking high doses of H₂ blockers for prolonged periods.

• Metformin (Glucophage®): Metformin may reduce serum folic acid and vitamin B₁₂ levels. These changes can lead to hyperhomocysteinemia, adding to the risk of cardiovascular disease in people with diabetes.^{[citation needed]} There are also rare reports of megaloblastic anemia in people who have taken metformin for 5 years or more. Reduced serum levels of vitamin B₁₂ occur in up to 30% of people taking metformin chronically.^[21][22] However, clinically significant deficiency is not likely to develop if dietary intake of vitamin B₁₂ is adequate. Deficiency can be corrected with vitamin B₁₂ supplements even if metformin is continued. The metformin-induced malabsorption of vitamin B₁₂ is reversible by oral calcium supplementation.^[23] The general clinical significance of metformin upon B₁₂ levels is as yet unknown.^[24]

• Neomycin: Absorption of vitamin B₁₂ can be reduced by neomycin, but prolonged use of large doses is needed to induce pernicious anemia. Supplements are not usually needed with normal doses.

• Nicotine: Nicotine can reduce serum vitamin B₁₂ levels. The need for vitamin B₁₂ supplementation has not been adequately studied.

• Nitrous oxide: Nitrous oxide inactivates the cobalamin form of vitamin B₁₂ by oxidation. Symptoms of vitamin B₁₂ deficiency, including sensory neuropathy, myelopathy, and encephalopathy, can occur within days or weeks of exposure to nitrous oxide anesthesia in people with subclinical vitamin B₁₂ deficiency. Symptoms are treated with high doses of vitamin B₁₂, but recovery can be slow and incomplete. People with normal vitamin B₁₂ levels have sufficient vitamin B₁₂ stores to make the effects of nitrous oxide insignificant, unless exposure is repeated and prolonged (such as recreational use). Vitamin B₁₂ levels should be checked in people with risk factors for vitamin B₁₂ deficiency prior to using nitrous oxide anesthesia.

• Phenytoin (Dilantin®), phenobarbital, primidone (Mysoline®): These anticonvulsants have been associated with reduced vitamin B₁₂ absorption, and reduced serum and cerebrospinal fluid levels in some patients. This may contribute to the megaloblastic anemia, primarily caused by folate deficiency, associated with these drugs. It's also suggested that reduced vitamin B₁₂ levels may contribute to the neuropsychiatric side effects of these drugs. Patients should be encouraged to maintain adequate dietary vitamin B₁₂ intake. Folate and vitamin B₁₂ status should be checked if symptoms of anemia develop.

• Proton pump inhibitors (PPIs): The PPIs include omeprazole (Prilosec®, Losec®), lansoprazole (Prevacid®), rabeprazole (Aciphex®), pantoprazole (Protonix®, Pantoloc®), and esomeprazole (Nexium®). The reduced secretion of gastric acid and pepsin produced by PPIs can reduce absorption of protein-bound (dietary) vitamin B₁₂, but not supplemental vitamin B₁₂. Gastric acid is needed to release vitamin B₁₂ from protein for absorption. Reduced vitamin B₁₂ levels may be more common with PPIs than with H2-blockers, because they are more likely to produce achlorhydria (complete absence of gastric acid secretion). However, clinically significant vitamin B₁₂ deficiency is unlikely, unless PPI therapy is prolonged (2 years or more) or dietary vitamin intake is low. Vitamin B₁₂ levels should be monitored in people taking high doses of PPIs for prolonged periods.

• Zidovudine (AZT, Combivir®, Retrovir®): Reduced serum vitamin B₁₂ levels may occur when zidovudine therapy is started. This adds to other factors that cause low vitamin B₁₂ levels in people with HIV, and might contribute to the hematological toxicity associated with zidovudine. However, data suggests vitamin B₁₂ supplements are not helpful for people taking zidovudine.

[edit] Interactions with herbs and dietary supplements

• Folic acid: Folic acid, particularly in large doses, can mask vitamin B₁₂ deficiency. In vitamin B₁₂ deficiency, folic acid can produce hematologic improvement in megaloblastic anemia, while allowing potentially irreversible neurological damage to progress. Vitamin B₁₂ status should be determined before folic acid is given as monotherapy.

• Potassium: Potassium supplements can reduce absorption of vitamin B₁₂ in some people. This effect has been reported with potassium chloride and, to a lesser extent, with potassium citrate. Potassium might contribute to vitamin B₁₂ deficiency in some people with other risk factors, but routine supplements are not necessary.

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[edit] External links

• Jane Higdon, "Vitamin B12", Micronutrient Information Center, Linus Pauling Institute
• NIH fact sheet
• Vitamin B12. Medline Plus (National Library of Medicine). Part of it was used for this article (US Government public domain), specially for drug and other interactions.
• Vitamin B₁₂ deficiency article in American Family Physician journal
• Vitamin B₁₂: Vital Nutrient for Good Health at the Weston A. Price Foundation

• Links to external chemical sources