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(Redirected from Vitamin B12)
'Cyanocobalamin' is a compound that is metabolized to a vitamin in the B complex commonly known as 'vitamin B' (or B for short).
Vitamin B is important for the normal functioning of the brain and nervous system and for the formation of blood. It is involved in the metabolism of every cell of the body, especially affecting the DNA synthesis and regulation but also fatty acid synthesis and energy production. Its effects are still not completely known.
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. This use is being contested because research indicates that it may not able to correct B12 deficiency in the brain effectively. Being an unnatural form of B12 it is misleading to equate it with the vitamin especially if it is not a fully effective supplement.
'Pseudo-B' refers to B-like substances which are found in certain organisms, including spirulina and other algae; however, these substances do not have B biological activity for humans.
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 Cobalt utilization, involve metal-carbon bonds.[1]
B cannot be made by plants or animals[2], 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 by Robert Burns Woodward[3][4] and Albert Eschenmoser[5][6], and remains one of the classic feats of total synthesis.
Species from the following genera are known to synthesize B: Aerobacter, Agrobacterium, Alcaligenes, Azotobacter, Bacillus, Clostridium, Corynebacterium, Flavobacterium, Micromonospora, Mycobacterium, Nocardia,
Propionibacterium, Protaminobacter, Proteus,
Pseudomonas, Rhizobium, Salmonella, Serratia, Streptomyces,
Streptococcus and Xanthomonas. Industrial production of
B is through fermentation of selected microorganisms.[7] The most used species are Pseudomonas denitrificans and Propionibacterium shermanii, often genetically engineered and grown under special conditions to enhance yield.
Coenzyme B's reactive C-Co bond participates in two types of enzyme-catalyzed reactions. [8]
#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.
#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)''. This functionality is lost in vitamin B deficiency, and can be measured clinically as an increased methylmalonic acid level ''in vitro''.
#MTR, a methyl transfer enzyme, which uses the MeB and reaction type 2 to catalyze the conversion of the amino acid Hcy into Met ''(for more see MTR's reaction mechanism)''. This functionality is lost in vitamin B deficiency, and can be measured clinically as an increased homocysteine level ''in vitro''. Increased homocysteine can also be diagnostic of a folic acid deficiency. There is some controversy over whether it is the reduced availability of methionine, or the reduced availability of THF (produced in the conversion of homocysteine to methionine) that is responsible for the reduced availability of 5,10-methylene-THF. 5,10-methylene-THF is involved in the synthesis of thymine, and hence reduced availability of 5,10-methylene-THF results in problems with DNA synthesis, and ultimately in ineffective production of blood cells[9].
These reactions have important secondary effects. The transformation of homocysteine to methionine is essential for the formation of transmethylating agent S-adenosylmethionine (SAMe). This substance is involved in the synthesis of myelin, which is essential for normal functioning of the nerves, which explains why B12 deficiency causes neuropathies. In addition, SAMe is involved in the manufacture of certain neurotransmitters, catecholamines and in the brain metabolism. These neurotransmitters are important for maintaining the mood, explaining why depression is associated with B12 deficiency.
The human physiology of vitamin B is complex, and therefore is prone to mishaps leading to vitamin B deficiency. The vitamin enters the digestive tract bound to proteins, known as salivary R-binders. Stomach proteolysis of these proteins requires an acid pH, and also requires proper pancreatic release of proteolytic enzymes. The vitamin B then attaches to gastric intrinsic factor, which is generated by the gastric parietal cells. The conjugated vitamin B-intrinsic factor complex can then be absorbed by the terminal ileum of the small bowel. Absorption of vitamin B therefore requires an intact and functioning stomach, exocrine pancreas, intrinsic factor, and small bowel. Problems with any one of these organs makes a vitamin B deficiency possible.
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.
Vitamin B12 deficiency can potentially cause severe and irreversible damage, especially to the brain and nervous system.
B can be supplemented in healthy subjects by oral pill; sublingual pill, liquid, or strip; or by injection. B is available singly or in combination with other supplements.
The Dietary Reference Intake for an adult range from 2 to 3 µg. The recommended optimal daily intake (ODI) is 10 to 15 µg.
Vitamin B is naturally found in foods of animal origin including meat, especially liver and shellfish, and milk products. Eggs are usually mentioned as a good source, however they also contain a factor that blocks absorption [10]. 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.
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 [11]. 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 B through dairy products, it may be found lacking in those practicing vegan diets who do not use multivitamin supplements or eat B fortified foods, such as fortified breakfast cereals, fortified soy-based products, and fortified energy bars. Claimed sources of B that have been shown through direct studies B12 in Tempeh, Seaweeds, Organic Produce, and Other Plant Foods of vegans to be inadequate or unreliable include, nori (a seaweed), barley grass, and human gut bacteria. People on a vegan raw food diet are also susceptible to B deficiency if no supplementation is used. The more alkaline intestines of vegans are able to metabolize
hydroxyl cobalamin preferentially, a more efficient cobalamin than cyanocobalamin.
A natural vegan source of B is the Chinese herb ''Dang Gui'' (''Angelica sinensis'') [12]. The herb is used in Traditional Chinese medicine for treating anemia.[1] Other potential sources of B 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 B. Another source of B is yeast spreads, such as Marmite, which are suitable for vegetarians and vegans.
The Vegan Society and Vegan Outreach, among others, recommend that vegans either consistently eat foods fortified with B or take a daily or weekly B12 supplement.[13][14]
Interestingly, certain insects such as termites have been found to contain B. [15]
Cyanocobalamin is also sometimes added to beverages including Diet Coke Plus and many energy drinks, in some cases with over 80 times the recommended intake.
Vitamin B supplements should be avoided in people sensitive or allergic to cobalamin, cobalt, or any other product ingredients.
★ 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.
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.
Hydroxycobalamin, also known as Vitamin B12a, 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[16]. 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. In the United States, the FDA has approved in 2006 the use of hydroxocobalamin for acute treatment of cyanide poisoning.
★ 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.
★ Hormonal contraception: 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. Metformin-associated vitamin B12 deficiency., Andrès E, Noel E, Goichot B, , , Arch Intern Med, 2002 Metformin and vitamin B12 deficiency., Gilligan M, , , Arch Intern Med, 2002 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.[17] The general clinical significance of metformin upon B levels is as yet unknown.[18]
★ 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 (such as recreational use). 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.
★ 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.
1. Bioorganometallics: Biomolecules, Labeling, Medicine; Jaouen, G., Ed. Wiley-VCH: Weinheim, 2006.3-527-30990-X.
2. Basiswissen Biochemie, G. Loeffler, , , , 2005,
3.
4. Woodward's Synthesis of Vitamin B12, Khan,AG and Easwaran,SV, , , Resonance, 2003
5.
6. Total Synthesis of Cobyric Acid: Historical Development and Recent Synthetic Innovations, Riether, D. and Mulzer, J., , , Eur. J. Org. Chem., 2003
7.
8. Biochemistry, Donald and Judith Voet, , , John Wiley & Sons Ltd., 1995, ISBN 0-471-58651-X
9. Morphology, biology and biochemistry of cobalamin- and folate-deficient bone marrow cells, Wickramasinghe SN, , , Baillieres Clin Haematol, 1995
10. Proc Soc Exp Biol Med, Sep;149(4):987-90;, Doscherholmen A et al. (1975), , , ,
11. Sharabi A, Cohen E, Sulkes J, Garty M. Replacement therapy for vitamin B12 deficiency: comparison between the sublingual and oral route. Br J Clin Pharmacol. 2003 Dec;56(6):635-8. PMID 14616423.
12. Huang KC. The Pharmacology of Chinese Herbs. 2nd ed. Boca Raton, FL: CRC Press; 1999. ISBN 0849316650.
13. Vitamin B12 in the Vegan Diet Reed Mangels, Ph.D., R.D.
14. Don't Vegetarians Have Trouble Getting Enough Vitamin B12?
15. Vitamin B-12 levels in selected insects, Wakayama EJ, Dillwith JW, Howard RW, Blomquist GJ, , , Insect Biochemistry, 1984
16. Hall AH, Rumack BH. Hydroxycobalamin/sodium thiosulfate as a cyanide antidote. J Emerg Med. 1987;5(2):115-21. PMID 3295013.
17. Bauman WA, Shaw S, Jayatilleke E, Spungen AM, Herbert V. Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. Diabetes Care. 2000 Sep;23(9):1227-31. PMID 10977010.
18. What effect does metformin have on vitamin B12 levels? Samantha Copp - Full report (DOC)
★
★ fact sheet at NIH
★ 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 B deficiency article in ''American Family Physician'' journal
★ Vitamin B: Vital Nutrient for Good Health at the Weston A. Price Foundation
★
'Cyanocobalamin' is a compound that is metabolized to a vitamin in the B complex commonly known as 'vitamin B' (or B for short).
Vitamin B is important for the normal functioning of the brain and nervous system and for the formation of blood. It is involved in the metabolism of every cell of the body, especially affecting the DNA synthesis and regulation but also fatty acid synthesis and energy production. Its effects are still not completely known.
Terminology
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. This use is being contested because research indicates that it may not able to correct B12 deficiency in the brain effectively. Being an unnatural form of B12 it is misleading to equate it with the vitamin especially if it is not a fully effective supplement.
'Pseudo-B' refers to B-like substances which are found in certain organisms, including spirulina and other algae; 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 Cobalt utilization, involve metal-carbon bonds.[1]
Synthesis
B cannot be made by plants or animals[2], 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 by Robert Burns Woodward[3][4] and Albert Eschenmoser[5][6], and remains one of the classic feats of total synthesis.
Species from the following genera are known to synthesize B: Aerobacter, Agrobacterium, Alcaligenes, Azotobacter, Bacillus, Clostridium, Corynebacterium, Flavobacterium, Micromonospora, Mycobacterium, Nocardia,
Propionibacterium, Protaminobacter, Proteus,
Pseudomonas, Rhizobium, Salmonella, Serratia, Streptomyces,
Streptococcus and Xanthomonas. Industrial production of
B is through fermentation of selected microorganisms.[7] The most used species are Pseudomonas denitrificans and Propionibacterium shermanii, often genetically engineered and grown under special conditions to enhance yield.
Functions
Coenzyme B's reactive C-Co bond participates in two types of enzyme-catalyzed reactions. [8]
#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.
#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)''. This functionality is lost in vitamin B deficiency, and can be measured clinically as an increased methylmalonic acid level ''in vitro''.
#MTR, a methyl transfer enzyme, which uses the MeB and reaction type 2 to catalyze the conversion of the amino acid Hcy into Met ''(for more see MTR's reaction mechanism)''. This functionality is lost in vitamin B deficiency, and can be measured clinically as an increased homocysteine level ''in vitro''. Increased homocysteine can also be diagnostic of a folic acid deficiency. There is some controversy over whether it is the reduced availability of methionine, or the reduced availability of THF (produced in the conversion of homocysteine to methionine) that is responsible for the reduced availability of 5,10-methylene-THF. 5,10-methylene-THF is involved in the synthesis of thymine, and hence reduced availability of 5,10-methylene-THF results in problems with DNA synthesis, and ultimately in ineffective production of blood cells[9].
These reactions have important secondary effects. The transformation of homocysteine to methionine is essential for the formation of transmethylating agent S-adenosylmethionine (SAMe). This substance is involved in the synthesis of myelin, which is essential for normal functioning of the nerves, which explains why B12 deficiency causes neuropathies. In addition, SAMe is involved in the manufacture of certain neurotransmitters, catecholamines and in the brain metabolism. These neurotransmitters are important for maintaining the mood, explaining why depression is associated with B12 deficiency.
Human digestion
The human physiology of vitamin B is complex, and therefore is prone to mishaps leading to vitamin B deficiency. The vitamin enters the digestive tract bound to proteins, known as salivary R-binders. Stomach proteolysis of these proteins requires an acid pH, and also requires proper pancreatic release of proteolytic enzymes. The vitamin B then attaches to gastric intrinsic factor, which is generated by the gastric parietal cells. The conjugated vitamin B-intrinsic factor complex can then be absorbed by the terminal ileum of the small bowel. Absorption of vitamin B therefore requires an intact and functioning stomach, exocrine pancreas, intrinsic factor, and small bowel. Problems with any one of these organs makes a vitamin B deficiency possible.
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.
Symptoms and damage from deficiency
Vitamin B12 deficiency can potentially cause severe and irreversible damage, especially to the brain and nervous system.
B can be supplemented in healthy subjects by oral pill; sublingual pill, liquid, or strip; or by injection. B is available singly or in combination with other supplements.
The Dietary Reference Intake for an adult range from 2 to 3 µg. The recommended optimal daily intake (ODI) is 10 to 15 µg.
Sources
Vitamin B is naturally found in foods of animal origin including meat, especially liver and shellfish, and milk products. Eggs are usually mentioned as a good source, however they also contain a factor that blocks absorption [10]. 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.
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 [11]. 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 B through dairy products, it may be found lacking in those practicing vegan diets who do not use multivitamin supplements or eat B fortified foods, such as fortified breakfast cereals, fortified soy-based products, and fortified energy bars. Claimed sources of B that have been shown through direct studies B12 in Tempeh, Seaweeds, Organic Produce, and Other Plant Foods of vegans to be inadequate or unreliable include, nori (a seaweed), barley grass, and human gut bacteria. People on a vegan raw food diet are also susceptible to B deficiency if no supplementation is used. The more alkaline intestines of vegans are able to metabolize
hydroxyl cobalamin preferentially, a more efficient cobalamin than cyanocobalamin.
A natural vegan source of B is the Chinese herb ''Dang Gui'' (''Angelica sinensis'') [12]. The herb is used in Traditional Chinese medicine for treating anemia.[1] Other potential sources of B 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 B. Another source of B is yeast spreads, such as Marmite, which are suitable for vegetarians and vegans.
The Vegan Society and Vegan Outreach, among others, recommend that vegans either consistently eat foods fortified with B or take a daily or weekly B12 supplement.[13][14]
Interestingly, certain insects such as termites have been found to contain B. [15]
Cyanocobalamin is also sometimes added to beverages including Diet Coke Plus and many energy drinks, in some cases with over 80 times the recommended intake.
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
★ 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.
Other medical uses
Hydroxycobalamin, also known as Vitamin B12a, 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[16]. 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. In the United States, the FDA has approved in 2006 the use of hydroxocobalamin for acute treatment of cyanide poisoning.
Interactions
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.
★ Hormonal contraception: 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. Metformin-associated vitamin B12 deficiency., Andrès E, Noel E, Goichot B, , , Arch Intern Med, 2002 Metformin and vitamin B12 deficiency., Gilligan M, , , Arch Intern Med, 2002 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.[17] The general clinical significance of metformin upon B levels is as yet unknown.[18]
★ 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 (such as recreational use). 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.
References
1. Bioorganometallics: Biomolecules, Labeling, Medicine; Jaouen, G., Ed. Wiley-VCH: Weinheim, 2006.3-527-30990-X.
2. Basiswissen Biochemie, G. Loeffler, , , , 2005,
3.
4. Woodward's Synthesis of Vitamin B12, Khan,AG and Easwaran,SV, , , Resonance, 2003
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6. Total Synthesis of Cobyric Acid: Historical Development and Recent Synthetic Innovations, Riether, D. and Mulzer, J., , , Eur. J. Org. Chem., 2003
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8. Biochemistry, Donald and Judith Voet, , , John Wiley & Sons Ltd., 1995, ISBN 0-471-58651-X
9. Morphology, biology and biochemistry of cobalamin- and folate-deficient bone marrow cells, Wickramasinghe SN, , , Baillieres Clin Haematol, 1995
10. Proc Soc Exp Biol Med, Sep;149(4):987-90;, Doscherholmen A et al. (1975), , , ,
11. Sharabi A, Cohen E, Sulkes J, Garty M. Replacement therapy for vitamin B12 deficiency: comparison between the sublingual and oral route. Br J Clin Pharmacol. 2003 Dec;56(6):635-8. PMID 14616423.
12. Huang KC. The Pharmacology of Chinese Herbs. 2nd ed. Boca Raton, FL: CRC Press; 1999. ISBN 0849316650.
13. Vitamin B12 in the Vegan Diet Reed Mangels, Ph.D., R.D.
14. Don't Vegetarians Have Trouble Getting Enough Vitamin B12?
15. Vitamin B-12 levels in selected insects, Wakayama EJ, Dillwith JW, Howard RW, Blomquist GJ, , , Insect Biochemistry, 1984
16. Hall AH, Rumack BH. Hydroxycobalamin/sodium thiosulfate as a cyanide antidote. J Emerg Med. 1987;5(2):115-21. PMID 3295013.
17. Bauman WA, Shaw S, Jayatilleke E, Spungen AM, Herbert V. Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. Diabetes Care. 2000 Sep;23(9):1227-31. PMID 10977010.
18. What effect does metformin have on vitamin B12 levels? Samantha Copp - Full report (DOC)
External links
★
★ fact sheet at NIH
★ 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 B deficiency article in ''American Family Physician'' journal
★ Vitamin B: Vital Nutrient for Good Health at the Weston A. Price Foundation
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