Cyanocobalamin

Cyanocobalamin
General
Molecular formula	C₆₃H₈₈CoN₁₄O₁₄P
Molar mass	1355.37 g/mol
Chemical infobox source ^* (all but the picture)

The name vitamin B (or B for short) is used in two different ways. In a broader sense it refers to a group of cobalt-containing compounds known as cobalamins - cyanocobalamin (an artefact 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, such as Spirulina spp. (blue-green algae, cyanobacteria). However, these substances do not have B biological activity for humans.

Structure

B is the most chemically complex of all the vitamins. B's structure is based on a corrin ring, which, although similar to the porphyrin ring found in heme, chlorophyll, and cytochrome, has two of the pyrrole rings directly bonded. The central metal ion is Co (cobalt). Four of the six coordinations are provided by the corrin ring nitrogens, and a fifth by a dimethylbenzimidazole group. The sixth coordination partner varies, 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 the only carbon-metal bond known in biology.

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.

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 alcochol, or an amine.
Methyl (-CH₃) group transfers between two molecules.

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

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)
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 bled dogs to make them anemic 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 as a treatment for cyanide poisoning, with a large amount (5-10 g) given intravenously. The treatment is marketed under the tradename Cyanokit . The mechanism of action is straightforward, the hydroxycobalamin hydroxide ligand is displaced by the toxic cyanide ion, and the resulting harmless B is excreted in urine.

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 stomach is vital to absorption of this vitamin. 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). 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.

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 Deficiency and Depression in Physically Disabled Older Women: Epidemiologic Evidence From the Women’s Health and Aging Study | journal= Am. J. Psychiatry| year= 2000| volume= 157| pages= 715–721| url= http://ajp.psychiatryonline.org/cgi/content/abstract/157/5/715| id= PMID 10784463}} and 2002 .

Traditionally, treatment for B deficiency was through intramuscular injections of cyanocobalamin. However, it has recently been appreciated that deficiency can be treated with oral B supplements when given in sufficient doses. When given in oral doses ranging from 0.1–100 mg daily, B can be absorbed in a pathway that does not require an intact ileum or intrinsic factor. 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.

Sources

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

While lacto-ovo vegetarians usually get enough B through dairy products or eggs, it may be found lacking in those practicing vegan diets who do not use multivitamin supplements or eat B fortified foods, such as fortified cereals (for example, Cheerios), fortified soy-based products, and fortified energy bars. Claimed sources of B that have been shown through direct studies of vegans to be inadequate or unreliable include spirulina (an algae), nori (a seaweed), barley grass, and human gut bacteria. Several studies of vegans on raw food diets show that raw food offers no special protection against B deficiency either. The only known vegan sources of substantial B, aside from multivitamin supplements and fortified foods, are the Chinese herb Dang Gui (Angelica sinensis), used for centuries for treating anemia, and certain brands of fortified nutritional yeast.

Interestingly, certain insects such as termites have been found to contain B.

Cyanocobalamin is also found in many energy drinks.

Allergies

Vitamin B12 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 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 is contraindicated in early Leber's disease, which is hereditary optic nerve atrophy. Vitamin B12 can cause severe and swift optic atrophy.

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 larger amounts of vitamin B12 during pregnancy.

Interactions

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 blockers: 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. 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. 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. A multivitamin preparation may also be valuable for some patients. Patients should be monitored for signs and symptoms of vitamin B12 and folic acid deficiency. People taking metformin chronically should be advised to include adequate amounts of vitamin B12 in their diet, and have their serum vitamin B12 and homocysteine levels checked annually.
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 (nitrous oxide abuse). 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.

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.
Vitamin C: Preliminary evidence suggests that vitamin C supplements can destroy dietary vitamin B12. However, other components of food, such as iron and nitrates, might counteract this effect. Clinical significance is unknown, and it can likely be avoided if vitamin C supplements are taken at least 2 hours after meals.

References

External links

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.
Oregon State fact sheet
Vitamin B deficiency article in American Family Physician journal
Vegan Society article
Vitamin B: Vital Nutrient for Good Health at the Weston A. Price Foundation
Vitamin B12 content in food USDA database sorted by Vitamin B12 content

B vitamins | Cobalt compounds | Organometallic chemistry

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