Cyanocobalamin

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

The name vitamin B 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 B, methylcobalamin (MeB) and 5-deoxyadenosylcobalamin (adenosylcobalamin - AdoB). In a more specific way, the term B is used to refer to only one of these forms, cyanocobalamin, which is the principal B form used for foods and in nutritional supplements.

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

Structure
B is the most chemically complex of all the vitamins. The structure of B 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 B 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.

Synthesis
B cannot be made by plants or by animals, as the only type of organisms that have the enzymes required for the synthesis of B are bacteria and archaea. The total synthesis of B was reported in 1973 by Robert Burns Woodward, and remains one of the classic feats of total synthesis.

Functions
Coenzyme B's reactive C-Co bond participates in two types of enzyme-catalyzed reactions.

In humans there are only two coenzyme B-dependent enzymes:
 * 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.
 * 1) MUT which uses the AdoB 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 MeB and reaction type 2 to catalyzes the conversion of the amino acid Hcy into Met (for more see MTR's reaction mechanism).

History as a treatment for anemia
B 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 B 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.

Other medical uses
Hydroxycobalamin is used in Europe both for vitamin B 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. The mechanism of action is straightforward, the hydroxycobalamin hydroxide ligand is displaced by the toxic cyanide ion, and the resulting harmless B complex is excreted in urine. The FDA has approved in 2006 the use of hydroxocobalamin for acute treatment of cyanide poisoning.

Deficiency
The usual daily intake in the Western diet is 5-7 µg (Food and Drug Administration (FDA) Daily Value ); the daily requirement is 1-2 µg. B 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 B, inadequate production of intrinsic factor (pernicious anemia), disorders of the terminal ileum resulting in malabsorption, or by competition for available B (such as fish tapeworms or bacteria present in blind loop syndrome).

Metformin can also be associated with vitamin B deficiency. Metformin is a common drug-induced cause of B deficiency. It is felt that metformin inhibits calcium-dependent ileal absorption of the B-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 B deficiency such as methylmalonic acid measurements. Nevertheless, the findings emphasize that neurologists should consider the possibility of B deficiency in diabetic patients with neurologic symptoms while taking metformin.

B 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 B deficiency and can be helpful if the diagnosis is unclear.

Neurological signs of B 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 B blood levels in elderly people in 2000 and 2002.

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

Treatment of B12 deficiency
Traditionally, treatment for B deficiency was through intramuscular injections of cyanocobalamin. However, it has been appreciated since the 1960s that deficiency can sometimes be treated with oral B supplements when given in sufficient doses. When given in oral doses ranging from 0.1–2 mg daily, B can be absorbed in a pathway that does not require an intact ileum or intrinsic factor. 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 B 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.

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

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 B followed by oral administration of folic acid 1.2mg plus vitamin B6 48mg and vitamin B 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 B (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 B 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 B 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 B in the form of cyanocobalamin is contraindicated in early Leber's disease, which is hereditary optic nerve atrophy. Vitamin B can cause severe and swift optic atrophy.

Pregnancy and breastfeeding
Vitamin B is likely safe when used orally in amounts that do not exceed the recommended dietary allowance (RDA). The RDA for vitamin B 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 B during pregnancy.

Interactions with drugs

 * Alcohol (ethanol): Excessive alcohol intake lasting longer than two weeks can decrease vitamin B absorption from the gastrointestinal tract.
 * Aminosalicylic acid (para-aminosalicylic acid, PAS, Paser): Aminosalicylic acid can reduce oral vitamin B 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 B 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 B in the gut, preventing its absorption. In people with bacterial overgrowth of the small bowel, antibiotics such as metronidazole (Flagyl®) can actually improve vitamin B status. The effects of most antibiotics on gastrointestinal bacteria are unlikely to have clinically significant effects on vitamin B levels.


 * Birth control pills: The data regarding the effects of oral contraceptives on vitamin B 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 B levels usually occurs. Lower vitamin B 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 B 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 B.


 * 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 B. Lower doses do not seem to have a significant effect on vitamin B absorption after 3 years of colchicine therapy. The significance of this interaction is unclear. Vitamin B 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 B. It is unlikely that this interaction will deplete body stores of vitamin B 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 B 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 B, but not of supplemental vitamin B. Gastric acid is needed to release vitamin B from protein for absorption. Clinically significant vitamin B 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 B 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 B levels. These changes can lead to hyperhomocysteinemia, adding to the risk of cardiovascular disease in people with diabetes. There are also rare reports of megaloblastic anemia in people who have taken metformin for 5 years or more. Reduced serum levels of vitamin B occur in up to 30% of people taking metformin chronically. However, clinically significant deficiency is not likely to develop if dietary intake of vitamin B is adequate. Deficiency can be corrected with vitamin B supplements even if metformin is continued. The metformin-induced malabsorption of vitamin B is reversible by oral calcium supplementation. The general clinical significance of metformin upon B levels is as yet unknown.


 * Neomycin: Absorption of vitamin B 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 B levels. The need for vitamin B supplementation has not been adequately studied.


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


 * Phenytoin (Dilantin®), phenobarbital, primidone (Mysoline®): These anticonvulsants have been associated with reduced vitamin B 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 B levels may contribute to the neuropsychiatric side effects of these drugs. Patients should be encouraged to maintain adequate dietary vitamin B intake. Folate and vitamin B 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 B, but not supplemental vitamin B. Gastric acid is needed to release vitamin B from protein for absorption. Reduced vitamin B 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 B deficiency is unlikely, unless PPI therapy is prolonged (2 years or more) or dietary vitamin intake is low. Vitamin B levels should be monitored in people taking high doses of PPIs for prolonged periods.


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

Interactions with herbs and dietary supplements

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


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