Vitamin B 1

Vitamin B

Vitamin B12

Systematic (IUPAC) name

α-(5,6-dimethylbenzimidazolyl)cobamidcyanide

Clinical data

AHFS/Drugs.com monograph [1]

Pregnancy cat. ?

Legal status POM (UK) OTC (US)

Routes oral, IV, IM

Pharmacokinetic data

Bioavailability readily absorbed in distal half of the ileum

Protein binding Very high to specific transcobalamins plasma proteinsBinding of hydroxocobalamin is slightly higher than cyanocobalamin.

Metabolism hepatic

Half-life Approximately 6 days(400 days in the liver)

Excretion renal

Identifiers

CAS number 68-19-9 [2] 

ATC code B03BA01 [3]

PubChem CID 5479203 [4]

DrugBank DB00115 [5]

Vitamin B 2

ChemSpider 10469504 [6] 

KEGG D00166 [7] 

ChEMBL CHEMBL1697777 [8] 

Chemical data

Formula C63H88CoN14O14P

Mol. mass 1355.37 g/mol

 (what is this?)   (verify) [9]

Vitamin B12

, vitamin B12 or vitamin B-12, also called cobalamin, is a water-soluble vitamin with a key role in thenormal functioning of the brain and nervous system, and for the formation of blood. It is one of the eight B vitamins.It is normally involved in the metabolism of every cell of the human body, especially affecting DNA synthesis andregulation, but also fatty acid synthesis and energy production. It is the largest and most structurally complicatedvitamin and can be produced industrially only through bacterial fermentation-synthesis.Vitamin B12 consists of a class of chemically related compounds (vitamers), all of which have vitamin activity. Itcontains the biochemically rare element cobalt. Biosynthesis of the basic structure of the vitamin is accomplishedonly by bacteria, but conversion between different forms of the vitamin can be accomplished in the human body. Acommon synthetic form of the vitamin, cyanocobalamin, does not occur in nature, but is used in manypharmaceuticals and supplements, and as a food additive, because of its stability and lower cost. In the body it isconverted to the physiological forms, methylcobalamin and adenosylcobalamin, leaving behind the cyanide, albeit inminimal concentration. More recently, hydroxocobalamin, methylcobalamin, and adenosylcobalamin can also befound in more expensive pharmacological products and food supplements. The extra utility of these is currentlydebated.Vitamin B12 was discovered from its relationship to the disease pernicious anemia, which is an autoimmune diseasein which parietal cells of the stomach responsible for secreting intrinsic factor are destroyed. Intrinsic factor iscrucial for the normal absorption of B12, so a lack of intrinsic factor, as seen in pernicious anemia, causes a vitaminB12 deficiency. Many other subtler kinds of vitamin B12 deficiency and their biochemical effects have since beenelucidated.[10]

TerminologyThe names vitamin B12, vitamin B12, or vitamin B-12, and the alternative name cobalamin, generally refer to allforms of the vitamin. Some medical practitioners have suggested that its use be split into two different categories,however.• In a broad sense, B12 refers to a group of cobalt-containing vitamer compounds known as cobalamins: these

include cyanocobalamin (an artifact formed from using activated charcoal, which always contains trace cyanide,to purify hydroxycobalamin), hydroxocobalamin (another medicinal form, produced by bacteria), and finally, thetwo naturally occurring cofactor forms of B12 in the human body: 5'-deoxyadenosylcobalamin(adenosylcobalamin—AdoB12), the cofactor of Methylmalonyl Coenzyme A mutase (MUT), andmethylcobalamin (MeB12), the cofactor of 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR).

• The term B12 may be properly used to refer to cyanocobalamin, the principal B12 form used for foods and in nutritional supplements. This ordinarily creates no problem, except perhaps in rare cases of eye nerve damage, where the body is only marginally able to use this form due to high cyanide levels in the blood due to cigarette smoking, and thus requires cessation of smoking, or else B12 given in another form, for the optic symptoms to abate. However, tobacco amblyopia is a rare enough condition that debate continues about whether or not it

Vitamin B 3

represents a peculiar B12 deficiency which is resistant to treatment with cyanocobalamin.Finally, so-called pseudo-B12 refers to B12-like substances which are found in certain organisms, including Spirulina(a cyanobacterium) and some algae. These substances are active in tests of B12 activity by highly sensitiveantibody-binding serum assay tests, which measure levels of B12 and B12-like compounds in blood. However, thesesubstances do not have B12 biological activity for humans, a fact which may pose a danger to vegans and others ondiets who may not ingest sufficient quantities of B12 producing bacteria, but who nevertheless may show normal"B12" levels in the standard immunoassay which has become the normal medical method for testing for B12deficiency.[11] A number of vegan sources of Vitamin B12 do exist, however, including some meat analogues (foodsthat are vegan that are made to resemble meat), some soy-based products and some brands of fortified cereals(SOURCE: http:/ / www. vrg. org/ nutrition/ b12. htm).

Medical usesVitamin B12 is used to treat vitamin B12 deficiency, cyanide poisoning, and hereditary deficiency of transcobalaminII.[12] It is also given as part of the Schilling test for detecting pernicious anemia.[12]

For cyanide poisoning, a large amount may be given intravenously, and sometimes in combination with sodiumthiosulfate.[13] The mechanism of action is straightforward: the hydroxycobalamin hydroxide ligand is displaced bythe toxic cyanide ion, and the resulting harmless B12 complex is excreted in urine. In the United States, the Food andDrug Administration approved (in 2006) the use of hydroxocobalamin for acute treatment of cyanide poisoning.[14]

High vitamin B12 level in elderly individuals may protect against brain atrophy or shrinkage associated withAlzheimer's disease and impaired cognitive function.[15]

High-dose administration of Vitamin B12 has been additionally validated to stimulate the activity of the body's TH1suppressor T-Cells, which then down-regulates the over-production of the allergen antibody IgE in allergicindividuals.[16][17]

Recommended intakeThe dietary reference intake for an adult ranges from 2 to 3 µg per day.[18]

Vitamin B12 is believed to be safe when used orally in amounts that do not exceed the recommended dietaryallowance (RDA). There have also been studies that showed no adverse consequences of doses above the RDA.[19]

The RDA for vitamin B12 in pregnant women is 2.6 µg per day and 2.8 µg during lactation periods.[20] There isinsufficient reliable information available about the safety of consuming greater amounts of vitamin B12 duringpregnancy.The Vegan Society, the Vegetarian Resource Group, and the Physicians Committee for Responsible Medicine,among others, recommend that vegans either consistently eat foods fortified with B12 or take a daily or weekly B12supplement.[21][22][23] Fortified breakfast cereals are a particularly valuable source of vitamin B12 for vegetariansand vegans. In addition, adults age 51 and older are recommended to consume B12 fortified food or supplements tomeet the RDA, because they are a population at an increased risk of deficiency.[24]

Vitamin B 4

DeficiencyVitamin B12 deficiency can potentially cause severe and irreversible damage, especially to the brain and nervoussystem. At levels only slightly lower than normal, a range of symptoms such as fatigue, depression, and poormemory may be experienced.[10] However, these symptoms by themselves are too nonspecific to diagnosedeficiency of the vitamin.Vitamin B12 deficiency can also cause symptoms of mania and psychosis.[25][26] Vitamin B12 deficiency can becaused by the metabolic disorder pernicious anemia.

Adverse effects• Vitamin B12 has extremely low toxicity and even taking it in enormous doses appears not to be harmful to healthy

individuals.[27][28]

• Hematologic: Peripheral vascular thrombosis has been reported. Treatment of vitamin B12 deficiency can unmaskpolycythemia vera, which is characterized by an increase in blood volume and the number of red blood cells. Thecorrection of megaloblastic anemia with vitamin B12 can result in fatal hypokalemia and gout in susceptibleindividuals, 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 ishereditary optic nerve atrophy. Cyanocobalamin can cause severe and swift optic atrophy, but other forms ofvitamin B12 are available. However, the sources of this statement are not clear, while an opposing view[29]

concludes: "The clinical picture of optic neuropathy associated with vitamin B12 deficiency shows similarity tothat of Leber's disease optic neuropathy. Both involve the nerve fibres of the papillomacular bundle. The presentcase reports suggest that optic neuropathy in patients carrying a primary LHON mtDNA mutation may beprecipitated by vitamin B12 deficiency. Therefore, known carriers should take care to have an adequate dietaryintake of vitamin B12 and malabsorption syndromes like those occurring in familial pernicious anaemia or aftergastric surgery should be excluded."

AllergiesVitamin B12 supplements in theory should be avoided in people sensitive or allergic to cobalamin, cobalt, or anyother product ingredients. However, direct allergy to a vitamin or nutrient is extremely rare, and if reported, othercauses should be sought.

Interactions• 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 g/day for severalmonths. 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 itsabsorption. In people with bacterial overgrowth of the small bowel, antibiotics such as metronidazole (Flagyl) canactually improve vitamin B12 status. The effects of most antibiotics on gastrointestinal bacteria are unlikely tohave clinically significant effects on vitamin B12 levels.

• Hormonal contraception: 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

Vitamin B 5

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 ifthis combination cannot be avoided.

• Cobalt irradiation: Cobalt irradiation of the small bowel can decrease gastrointestinal (GI) absorption of vitaminB12.

• Colchicine: Colchicine in doses of 1.9 to 3.9 mg/day can disrupt normal intestinal mucosal function, leading tomalabsorption of several nutrients, including vitamin B12. Lower doses do not seem to have a significant effect onvitamin B12 absorption after 3 years of colchicine therapy. The significance of this interaction is unclear. VitaminB12 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 to decreasecholesterol, can decrease gastrointestinal (GI) absorption of vitamin B12. It is unlikely this interaction will depletebody stores of vitamin B12 unless there are other factors contributing to deficiency. In a group of children treatedwith cholestyramine for up to 2.5 years, there was not any change in serum vitamin B12 levels. Routinesupplements 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 ofprotein-bound (dietary) vitamin B12, but not of supplemental vitamin B12. Gastric acid is needed to releasevitamin B12 from protein for absorption. Clinically significant vitamin B12 deficiency and megaloblastic anemiaare unlikely, unless H2 blocker therapy is prolonged (2 years or more), or the person's diet is poor. It is also morelikely if the person is rendered achlorhydric(with complete absence of gastric acid secretion), which occurs morefrequently with proton pump inhibitors than H2 blockers. Vitamin B12 levels should be monitored in people takinghigh doses of H2 blockers for prolonged periods.

• Metformin (Glucophage): Metformin may reduce serum folic acid and vitamin B12 levels. These changes can leadto hyperhomocysteinemia, adding to the risk of cardiovascular disease in people with diabetes. There are also rarereports of megaloblastic anemia in people who have taken metformin for five years or more. Reduced serumlevels of vitamin B12 occur in up to 30% of people taking metformin chronically.[30][31] However, clinicallysignificant deficiency is not likely to develop if dietary intake of vitamin B12 is adequate. Deficiency can becorrected with vitamin B12 supplements even if metformin is continued. The metformin-induced malabsorption ofvitamin B12 is reversible by oral calcium supplementation.[32] The general clinical significance of metformin uponB12 levels is as yet unknown.[33]

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

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

• Nitrous oxide: Nitrous oxide inactivates the cobalamin form of vitamin B12 by oxidation. Symptoms of vitaminB12 deficiency, including sensory neuropathy, myelopathy, and encephalopathy, can occur within days or weeksof exposure to nitrous oxide anesthesia in people with subclinical vitamin B12 deficiency. Symptoms are treatedwith high doses of vitamin B12, but recovery can be slow and incomplete. People with normal vitamin B12 levelshave sufficient vitamin B12 stores to make the effects of nitrous oxide insignificant, unless exposure is repeatedand prolonged (such as recreational use). Vitamin B12 levels should be checked in people with risk factors forvitamin B12 deficiency prior to using nitrous oxide anesthesia. Chronic nitrous oxide B12 poisoning (usually fromuse of nitrous oxide as a recreational drug), however, may result in B12 functional deficiency even with normalmeasured blood levels of B12.[34]

• Phenytoin (Dilantin), phenobarbital, primidone (Mysoline): These anticonvulsants have been associated with reduced vitamin B12 absorption, and reduced serum and cerebrospinal fluidlevels in some patients. This may contribute to the megaloblastic anemia, primarily caused by folate deficiency, associated with these drugs. It is

Vitamin B 6

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 statusshould 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 ofgastric acid and pepsin produced by PPIs can reduce absorption of protein-bound (dietary) vitamin B12, but notsupplemental vitamin B12. Gastric acid is needed to release vitamin B12 from protein for absorption. Reducedvitamin B12 levels may be more common with PPIs than with H2-blockers, because they are more likely toproduce achlorhydria (complete absence of gastric acid secretion). However, clinically significant vitamin B12deficiency is unlikely, unless PPI therapy is prolonged (2 years or more) or dietary vitamin intake is low. VitaminB12 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 isstarted. This adds to other factors that cause low vitamin B12 levels in people with HIV, and might contribute tothe hematological toxicity associated with zidovudine. However, the data suggest vitamin B12 supplements arenot helpful for people taking zidovudine.

• Folic acid: Folic acid, particularly in large doses, can mask vitamin B12 deficiency by completely correctinghematological abnormalities. In vitamin B12 deficiency, folic acid can produce complete resolution of thecharacteristic megaloblastic anemia, while allowing potentially irreversible neurological damage (from continuedinactivity of methylmalonyl mutase) to progress. Thus, vitamin B12 status should be determined before folic acidis given as monotherapy.

• Potassium: Potassium supplements can reduce absorption of vitamin B12 in some people. This effect has beenreported with potassium chloride and, to a lesser extent, with potassium citrate. Potassium might contribute tovitamin B12 deficiency in some people with other risk factors, but routine supplements are not necessary.[35]

StructureVitamin B12 is a collection of cobalt and corrin ring molecules which are defined by their particular vitamin functionin the body. All of the substrate cobalt-corrin molecules from which B12 is made, must be synthesized by bacteria.However, after this synthesis is complete, the body has a limited power to convert any form of B12 to another, bymeans of enzymatically removing certain prosthetic chemical groups from the cobalt atom. The various forms(vitamers) of B12 are all deeply red colored, due to the color of the cobalt-corrin complex.Cyanocobalamin is one such "vitamer" in this B complex, because it can be metabolized in the body to an activeco-enzyme form. However, the cyanocobalamin form of B12 does not occur in nature normally, but is a byproduct ofthe fact that other forms of B12 are avid binders of cyanide (-CN) which they pick up in the process of activatedcharcoal purification of the vitamin after it is made by bacteria in the commercial process.[36] Since thecyanocobalamin form of B12 is easy to crystallize and is not sensitive to air-oxidation, it is typically used as a formof B12 for food additives and in many common multivitamins. However, this form is not perfectly synonymous withB12, in as much as a number of substances (vitamers) have B12 vitamin activity and can properly be labeled vitaminB12, and cyanocobalamin is but one of them. (Thus, all cyanocobalamin is vitamin B12, but not all vitamin B12 iscyanocobalamin).[37] Pure cyanocobalamin possesses the deep pink color associated with most octahedral cobalt(II)complexes and the crystals are well formed and easily grown up to millimeter size.Hydroxocobalamin is another form of B12 commonly encountered in pharmacology, but which is not normally present in the human body. Hydroxocobalamin is sometimes denoted B12a. This form of B12 is the form produced by bacteria, and is what is converted to cyanocobalmin in the commercial charcoal filtration step of production. Hydroxocobalamin has an avid affinity for cyanide ion and has been used as an antidote to cyanide poisoning. It is supplied typically in water solution for injection. Hydroxocobalamin is thought to be converted to the active enzymic forms of B12 more easily than cyanocobalamin, and since it is little more expensive than cyanocobalamin, and has

Vitamin B 7

longer retention times in the body, has been used for vitamin replacement in situations where added reassurance ofactivity is desired. Intramuscular administration of hydroxocobalamin is also the preferred treatment for pediatricpatients with intrinsic cobalamin metabolic diseases, for vitamin B12 deficient patients with tobacco amblyopia(which is thought to perhaps have a component of cyanide poisoning from cyanide in cigarette smoke); and fortreatment of patients with pernicious anemia who have optic neuropathy.B12 is the most chemically complex of all the vitamins. The structure of B12 is based on a corrin ring, which issimilar to the porphyrin ring found in heme, chlorophyll, and cytochrome. The central metal ion is cobalt. Four of thesix coordination sites are provided by the corrin ring, and a fifth by a dimethylbenzimidazole group. The sixthcoordination site, the center of reactivity, is variable, being a cyano group (-CN), a hydroxyl group (-OH), a methylgroup (-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. Historically, the covalent C-Co bond is one of firstexamples of carbon-metal bonds to be discovered in biology. The hydrogenases and, by necessity, enzymesassociated with cobalt utilization, involve metal-carbon bonds.[38]

Adenosylcobalamin (adoB12) and methylcobalamin (MeB12) are the two enzymatically-active cofactor forms ofB12 that naturally occur in the body. Most of the body's reserves are stored as adoB12 in the liver.

Synthesis and industrial productionNeither plants nor animals are independently capable of constructing vitamin B12.[39] Only bacteria and archaea[40]

have the enzymes required for its synthesis. The total synthesis of B12 was reported by Robert Burns Woodward[41]

and Albert Eschenmoser in 1972,[42][43] and remains one of the classic feats of organic synthesis. Species from thefollowing genera are known to synthesize B12: Acetobacterium, Aerobacter, Agrobacterium, Alcaligenes,Azotobacter, Bacillus, Clostridium, Corynebacterium, Flavobacterium, Lactobacillus, Micromonospora,Mycobacterium, Nocardia, Propionibacterium, Protaminobacter, Proteus, Pseudomonas, Rhizobium, Salmonella,Serratia, Streptomyces, Streptococcus and Xanthomonas.Industrial production of B12 is through fermentation of selected microorganisms.[44] Streptomyces griseus, abacterium once thought to be a yeast, was the commercial source of vitamin B12 for many years.[45][46] The speciesPseudomonas denitrificans and Propionibacterium shermanii are more commonly used today.[47] These arefrequently grown under special conditions to enhance yield, and at least one company, Rhône-Poulenc of France,which has merged into Sanofi-Aventis, used genetically engineered versions of one or both of these species. Since anumber of species of Propionibacterium produce no exotoxins or endotoxins and are generally regarded as safe(have been granted GRAS status) by the Food and Drug Administration of the United States, they are presently theFDA-preferred bacterial fermentation organisms for vitamin B12 production.[48]

The total world production of vitamin B12, by four companies (the French Sanofi-Aventis and three Chinesecompanies) is said to have been 35 tonnes in 2008.[49] Most of this production is used as an additive to animalfeed.[50]

See cyanocobalamin for discussion of the chemical preparation of reduced-cobalt vitamin analogs and preparation ofphysiological forms of the vitamin such as adenosylcobalamin and methylcobalamin.

Vitamin B 8

Mechanism of action

Metabolism of folic acid. The role of Vitamin B12 is seen at bottom-left.

Vitamin B12 normally plays a significantrole in the metabolism of every cell of thebody, especially affecting the DNAsynthesis and regulation but also fatty acidsynthesis and energy production.[51]

However, many (though not all) of theeffects of functions of B12 can be replacedby sufficient quantities of folic acid (vitaminB9), since B12 is used to regenerate folate inthe body. Most vitamin B12 deficiencysymptoms are actually folate deficiencysymptoms, since they include all the effectsof pernicious anemia and megaloblastosis,which are due to poor synthesis of DNAwhen the body does not have a proper supply of folic acid for the production of thymine.[52] When sufficient folicacid is available, all known B12 related deficiency syndromes normalize, save those narrowly connected with thevitamin B12-dependent enzymes Methylmalonyl Coenzyme A mutase, and 5-methyltetrahydrofolate-homocysteinemethyltransferase (MTR), also known as methionine synthase; and the buildup of their respective substrates(methylmalonic acid, MMA) and homocysteine.

Coenzyme B12's reactive C-Co bond participates in three main types of enzyme-catalyzed reactions.[53][54]

1. Isomerases. Rearrangements in which a hydrogen atom is directly transferred between two adjacent atoms withconcomitant exchange of the second substituent, X, which may be a carbon atom with substituents, an oxygenatom of an alcohol, or an amine. These use the adoB12 (adenosylcobalamin) form of the vitamin.

2. Methyltransferases. Methyl (-CH3) group transfers between two molecules. These use MeB12(methylcobalamin) form of the vitamin.

3. Dehalogenases. Reactions in which a halogen atom is removed from an organic molecule. Enzymes in this classhave not been identified in humans.

In humans, two major coenzyme B12-dependent enzyme families corresponding to the first two reaction types, areknown. These are typified by the following two enzymes:1. MUT is an isomerase 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 inthe extraction of energy from proteins and fats (for more see MUT's reaction mechanism). This functionality islost in vitamin B12 deficiency, and can be measured clinically as an increased methylmalonic acid (MMA) level.Unfortunately, an elevated MMA, though sensitive to B12 deficiency, is probably overly sensitive, and not all whohave it actually have B12 deficiency. For example, MMA is elevated in 90–98% of patients with B12 deficiency;however 20–25% of patients over the age of 70 have elevated levels of MMA, yet 25–33% of them do not haveB12 deficiency. For this reason, assessment of MMA levels is not routinely recommended in the elderly. There isno "gold standard" test for B12 deficiency because as a B12 deficiency occurs, serum values may be maintainedwhile tissue B12 stores become depleted. Therefore, serum B12 values above the cut-off point of deficiency do notnecessarily indicate adequate B12 status[24] The MUT function cannot be affected by folate supplementation,which is necessary for myelin synthesis (see mechanism below) and certain other functions of the central nervoussystem. Other functions of B12 related to DNA synthesis related to MTR dysfunction (see below) can often becorrected with supplementation with the vitamin folic acid, but not the elevated levels of homocysteine, which isnormally converted to methionine by MTR.

Vitamin B 9

2. MTR, also known as methionine synthase, is a methyltransferase enzyme, which uses the MeB12 and reactiontype 2 to catalyze the conversion of the amino acid homocysteine (Hcy) back into methionine (Met) (for more seeMTR's reaction mechanism).[55] This functionality is lost in vitamin B12 deficiency, and can be measuredclinically as an increased homocysteine level in vitro. Increased homocysteine can also be caused by a folic aciddeficiency, since B12 helps to regenerate the tetrahydrofolate (THF) active form of folic acid. Without B12, folateis trapped as 5-methyl-folate, from which THF cannot be recovered unless a MTR process reacts the5-methyl-folate with homocysteine to produce methionine and THF, thus decreasing the need for fresh sources ofTHF from the diet. THF may be produced in the conversion of homocysteine to methionine, or may be obtainedin the diet. It is converted by a non-B12-dependent process to 5,10-methylene-THF, which is involved in thesynthesis of thymine. Reduced availability of 5,10-methylene-THF results in problems with DNA synthesis, andultimately in ineffective production cells with rapid turnover, in particular blood cells, and also intestinal wallcells which are responsible for absorption. The failure of blood cell production results in the once-dreaded andfatal disease, pernicious anemia. All of the DNA synthetic effects, including the megaloblastic anemia ofpernicious anemia, resolve if sufficient folate is present (since levels of 5,10-methylene-THF still remain adequatewith enough dietary folate). Thus the best-known "function" of B12 (that which is involved with DNA synthesis,cell-division, and anemia) is actually a facultative function which is mediated by B12-conservation of an activeform of folate which is needed for efficient DNA production.[56] Other cobalamin-requiring methyltransferaseenzymes are also known in bacteria, such as Me-H4-MPT, coenzyme M methyl transferase.

Enzyme functionIf folate is present in quantity, then of the two absolutely vitamin B12-dependent enzyme-family reactions in humans,the MUT-family reactions show the most direct and characteristic secondary effects, focusing on the nervous system(see below). This is because the MTR (methyltransferase-type) reactions are involved in regenerating folate, and thusare less evident when folate is in good supply.Since the late 1990s, folic acid has begun to be added to fortify flour in many countries, so folate deficiency is nowmore rare. At the same time, since DNA synthetic-sensitive tests for anemia and erythrocyte size are routinely donein even simple medical test clinics (so that these folate-mediated biochemical effects are more often directlydetected), the MTR-dependent effects of B12 deficiency are becoming apparent not as anemia due to DNA-syntheticproblems (as they were classically), but now mainly as a simple and less obvious elevation of homocysteine in theblood and urine (homocysteinuria). This condition may result in long term damage to arteries and in clotting (strokeand heart attack), but this effect is difficult to separate from other common processes associated with atherosclerosisand aging.The specific myelin damage resulting from B12 deficiency, even in the presence of adequate folate and methionine,is more specifically and clearly a vitamin deficiency problem. It has been connected to B12 most directly by reactionsrelated to MUT, which is absolutely required to convert methylmalonyl coenzyme A into succinyl coenzyme A.Failure of this second reaction to occur results in elevated levels of MMA, a myelin destabilizer. Excessive MMAwill prevent normal fatty acid synthesis, or it will be incorporated into fatty acid itself rather than normal malonicacid. If this abnormal fatty acid subsequently is incorporated into myelin, the resulting myelin will be too fragile, anddemyelination will occur. Although the precise mechanism(s) are not known with certainty, the result is subacutecombined degeneration of central nervous system and spinal cord.[57] Whatever the cause, it is known that B12deficiency causes neuropathies, even if folic acid is present in good supply, and therefore anemia is not present.Vitamin B12-dependent MTR reactions may also have neurological effects, through an indirect mechanism. Adequate methionine (which, like folate, must otherwise be obtained in the diet, if it is not regenerated from homocysteine by a B12 dependent reaction) is needed to make S-adenosyl-methionine (SAMe), which is in turn necessary for methylation of myelin sheath phospholipids. Although production of SAMe is not B12 dependent, help in recycling for provision of one adequate substrate for it (the essential amino acid methionine) is assisted by B12. In

Vitamin B 10

addition, SAMe is involved in the manufacture of certain neurotransmitters, catecholamines and in brain metabolism.These neurotransmitters are important for maintaining mood, possibly explaining why depression is associated withB12 deficiency. Methylation of the myelin sheath phospholipids may also depend on adequate folate, which in turn isdependent on MTR recycling, unless ingested in relatively high amounts.

Absorption and distributionThe human physiology of vitamin B12 is complex, and therefore is prone to mishaps leading to vitamin B12deficiency. Protein-bound vitamin B12 must be released from the proteins by the action of digestive proteases in boththe stomach and small intestine.[58] Gastric acid releases the vitamin from food particles; therefore antacid andacid-blocking medications (especially proton-pump inhibitors) may inhibit absorption of B12. In addition someelderly people produce less stomach acid as they age thereby increasing their probability of B12 deficiencies.[59]

B12 taken in a low-solubility, non-chewable supplement pill form may bypass the mouth and stomach and not mixwith gastric acids, but these are not necessary for the absorption of free B12 not bound to protein.R-proteins (such as haptocorrins and cobalaphilin) are B12 binding proteins that are produced in the salivary glands.They must wait until B12 has been freed from proteins in food by pepsin in the stomach. B12 then binds to theR-Proteins to avoid degradation of it in the acidic environment of the stomach.[60]

This pattern of secretion of a binding protein secreted in a previous digestive step, is repeated once more beforeabsorption. The next binding protein is intrinsic factor (IF), a protein synthesized by gastric parietal cells that issecreted in response to histamine, gastrin and pentagastrin, as well as the presence of food. In the duodenum,proteases digest R-proteins and release B12, which then binds to IF, to form a complex (IF/B12). B12 must beattached to IF for it to be absorbed, as receptors on the enterocytes in the terminal ileum of the small bowel onlyrecognize the B12-IF complex; in addition, intrinsic factor protects the vitamin from catabolism by intestinalbacteria.Absorption of food vitamin B12 thus requires an intact and functioning stomach, exocrine pancreas, intrinsic factor,and small bowel. Problems with any one of these organs makes a vitamin B12 deficiency possible. Individuals wholack intrinsic factor have a decreased ability to absorb B12. In pernicious anemia, there is a lack of IF due toautoimmune atrophic gastritis, in which antibodies form against parietal cells. Antibodies may alternately formagainst and bind to IF, inhibiting it from carrying out its B12 protective function. Due to the complexity of B12absorption, geriatric patients, many of whom are hypoacidic due to reduced parietal cell function, have an increasedrisk of B12 deficiency.[61] This results in 80–100% excretion of oral doses in the feces versus 30–60% excretion infeces as seen in individuals with adequate IF.[61]

Once the IF/B12 complex is recognized by specialized ileal receptors, it is transported into the portal circulation. Thevitamin is then transferred to transcobalamin II (TC-II/B12), which serves as the plasma transporter. Hereditarydefects in production of the transcobalamins and their receptors may produce functional deficiencies in B12 andinfantile megaloblastic anemia, and abnormal B12 related biochemistry, even in some cases with normal blood B12levels.[62] For the vitamin to serve inside cells, the TC-II/B12 complex must bind to a cell receptor, and beendocytosed. The transcobalamin-II is degraded within a lysosome, and free B12 is finally released into thecytoplasm, where it may be transformed into the proper coenzyme, by certain cellular enzymes (see above).It's important to note that investigations into the intestinal absorption of B12 point out that the upper limit per singledose, under normal conditions, is about 1.5 µg: "Studies in normal persons indicated that about 1.5 µg is assimilatedwhen a single dose varying from 5 to 50 µg is administered by mouth. In a similar study Swendseid et al. stated thatthe average maximum absorption was 1.6 µg [...]" [63]The total amount of vitamin B12 stored in body is about 2–5 mg in adults. Around 50% of this is stored in the liver.[24] Approximately 0.1% of this is lost per day by secretions into the gut, as not all these secretions are reabsorbed. Bile is the main form of B12 excretion; however, most of the B12 secreted in the bile is recycled via

Vitamin B 11

enterohepatic circulation.[24] Due to the extremely efficient enterohepatic circulation of B12, the liver can storeseveral years’ worth of vitamin B12; therefore, nutritional deficiency of this vitamin is rare. How fast B12 levelschange depends on the balance between how much B12 is obtained from the diet, how much is secreted and howmuch is absorbed. B12 deficiency may arise in a year if initial stores are low and genetic factors unfavourable, ormay not appear for decades. In infants, B12 deficiency can appear much more quickly.[64]

HistoryB12 deficiency is the cause of pernicious anemia, an anemic disease that was usually fatal and had unknown etiologywhen it was first described in medicine. The cure, and B12, were discovered by accident. George Whipple had beendoing experiments in which he induced anemia in dogs by bleeding them, and then fed them various foods toobserve which diets allowed them fastest recovery from the anemia produced. In the process, he discovered thatingesting large amounts of liver seemed to most-rapidly cure the anemia of blood loss. Thus, he hypothesized thatliver ingestion might treat pernicious anemia. He tried this and reported some signs of success in 1920.After a series of careful clinical studies, George Richards Minot and William Murphy set out to partly isolate thesubstance in liver which cured anemia in dogs, and found that it was iron. They also found that an entirely differentliver substance cured pernicious anemia in humans, that had no effect on dogs under the conditions used. Thespecific factor treatment for pernicious anemia, found in liver juice, had been found by this coincidence. Minot andMurphy reported these experiments in 1926. This was the first real progress with this disease. Despite this discovery,for several years patients were still required to eat large amounts of raw liver or to drink considerable amounts ofliver juice.In 1928, the chemist Edwin Cohn prepared a liver extract that was 50 to 100 times more potent than the natural liverproducts. The extract was the first workable treatment for the disease. For their initial work in pointing the way to aworking treatment, Whipple, Minot, and Murphy shared the 1934 Nobel Prize in Physiology or Medicine.These events in turn eventually led to discovery of the soluble vitamin, called vitamin B12, in the liver juice. Thevitamin in liver extracts was not isolated until 1948 by the contributions of chemists Mary Shaw Shorb[65] and KarlA. Folkers of the United States and Alexander R. Todd of Great Britain. In 1947, while working for the PoultryScience Department at the University of Maryland, Mary Shorb (in a collaborative project with Folkers and Merck)was provided with a $400 grant to develop the LLD assay. The LLD assay led to the purification andcharacterization of Vitamin B12 as it caused rapid isolation of the anti-pernicious anemia factor. For this discovery,in 1949 Mary Shorb and Karl Folkers received the Mead Johnson Award from the American Society of NutritionalSciences.[65]

The chemical structure of the molecule was determined by Dorothy Crowfoot Hodgkin and her team in 1956, basedon crystallographic data.[66] Eventually, methods of producing the vitamin in large quantities from bacteria cultureswere developed in the 1950s, and these led to the modern form of treatment for the disease.

Sources

Foods

Vitamin B 12

Sources of Vitamin B12

Food[67] µg vitamin B

12/100g

Panfried beef liver 83.1

Simmered turkey giblets 33.2

Braunschweiger pork liver sausage 20.1

Raw Pacific oysters 16.0

Cooked Alaska king crab 11.5

Raw clams 11.3

Simmered chicken giblets 9.4

Cheese 3.3

Beef (uncooked sirloin) 1.15

Egg (raw, whole chicken's egg) 0.89

Whole cow's milk 0.45

Raw chicken breast (see Salmonellosis) 0.20

Ultimately, animals must obtain vitamin B12 directly or indirectly from bacteria, and these bacteria may inhabit asection of the gut which is distal to the section where B12 is absorbed. Thus, herbivorous animals must either obtainB12 from bacteria in their rumens, or (if fermenting plant material in the hindgut) by reingestion of cecotrope feces.Plants pulled from the ground and not washed scrupulously may contain remnants of B12 acquired from the bacteriapresent in the surrounding soil.[68] B12 is also found in lakes, before the water is sanitized.[69]

Vitamin B12 is found in foods that come from animals, including fish and shellfish, meat (especially liver), poultry,eggs, milk, and milk products.[10] Eggs are often mentioned as a good B12 source, but they also contain a factor thatblocks absorption. However, the binding capacity of heat treated egg yolks and egg whites is markedly diminishedafter heat treatment.[70] Certain insects such as termites contain B12 produced by their gut bacteria, in a wayanalogous to ruminant animals.[71] An NIH Fact Sheet lists a variety of food sources of vitamin B12.[10]

While lacto-ovo vegetarians usually get enough B12 through consuming dairy products, vegans will lack B12 unlessthey consume B12-containing dietary supplements or B12-fortified foods. Examples of fortified foods includefortified breakfast cereals, fortified soy products, fortified energy bars, and fortified nutritional yeast. According tothe UK Vegan Society, the present consensus is that any B12 present in plant foods is likely to be unavailable tohumans because B12 analogues can compete with B12 and inhibit metabolism.[72][73]

Some critics of meat-eating and nutritionists cite that the human intestinal tract also contains B12-producingbacteria[74], however, it is unclear whether this is in sufficient amounts for proper nutrition.Claimed sources of B12 that have been shown to be inadequate or unreliable through direct studies[75] of vegansinclude laver (a seaweed), and barley grass.[76] Saccharomyces cerevisiae, a strain of nutritional yeast, often containsvitamin B12, either naturally occurring or as an additive. Because nutritional yeast is often used by vegans, whousually need to supplement their diets with vitamin B12, there has been confusion about the source of the B12 innutritional yeast. Although yeasts are closer to animals than plants in their genomes and metabolisms, they are fungiand cannot produce B12, which is only naturally produced by bacteria. Some brands of nutritional yeast, though notall, are fortified with vitamin B12. When fortified, the vitamin B12 is produced separately (commonlycyanocobalamin) and then added to the yeast.[77] Although some species of bacteria that can produce B12 couldpotentially grow along with S. cerevisiae in the wild, commercially produced nutritional yeast is grown in controlledconditions that would normally not allow those bacteria to grow. Therefore, nutritional yeast should not be reliedupon as a source of B12 unless it is fortified with B12 during processing.[78]

Vitamin B 13

SupplementsVitamin B12 is provided as a supplement in many processed foods, and is also available in vitamin pill form,including multi-vitamins. Vitamin B12 can be supplemented in healthy subjects also by liquid, transdermal patch,nasal spray, or injection and is available singly or in combination with other supplements. It is a common ingredientin energy drinks and energy shots, usually at several times the minimum recommended daily allowance of B12.Vitamin B12 supplements are effective for preventing deficiencies, especially in vegetarians, and are often marketedas weight loss supplements.[79] However, no scientific studies have shown that B12 is effective for weight loss.[80]

Cyanocobalamin is converted to its active forms, first hydroxocobalamin and then methylcobalamin andadenosylcobalamin in the liver.The sublingual route, in which B12 is presumably or supposedly absorbed more directly under the tongue, has notproven to be necessary or helpful, even though a number of lozenges, pills, and even a lollipop designed forsublingual absorption, are being marketed. A 2003 study found no significant difference in absorption for serumlevels from oral vs. sublingual delivery of 0.5 mg of cobalamin.[81] Sublingual methods of replacement are effectiveonly because of the typically high doses (0.5 mg), which are swallowed, not because of placement of the tablet. Asnoted below, such very high doses of oral B12 may be effective as treatments, even if gastro-intestinal tractabsorption is impaired by gastric atrophy (pernicious anemia).Injection and patches are sometimes used if digestive absorption is impaired, but there is evidence that this course ofaction may not be necessary with modern high potency oral supplements (such as 0.5 to 1 mg or more). Evenpernicious anemia can be treated entirely by the oral route.[82][83][84] These supplements carry such large doses ofthe vitamin that 1% to 5% of high oral doses of free crystalline B12 is absorbed along the entire intestine by passivediffusion.However, if the patient has inborn errors in the methyltransfer pathway (cobalamin C disease, combinedmethylmalonic aciduria and homocystinuria), treatment with intravenous, intramuscular hydroxocobalamin ortransdermal B12 is needed.[85][86][87][88][89]

Non-cyano forms as supplements

Recently sublingual methylcobalamin has become available in 1 mg tablets. Such tablets have higher bioavailabilitythan the older cyanocobalamin. No cyanide is released with methylcobolamin, although the amount of cyanide (2%of the weight, or 20 micrograms cyanide in a 1 mg cyanocobalamin tab) is far less than ingested in many naturalfoods. Although the safety of cyanocobalamin has not been seriously questioned, the safety of the other types is alsowell-established.[90]

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Vitamin B 14

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[86] Roze E, Gervais D, Demeret S, et al. (2003). "Neuropsychiatric disturbances in presumed late-onset cobalamin C disease". Arch. Neurol. 60(10): 1457–62. doi:10.1001/archneur.60.10.1457. PMID 14568819.

[87] Thauvin-Robinet C, Roze E, Couvreur G, et al. (2008). "The adolescent and adult form of cobalamin C disease: clinical and molecularspectrum". J. Neurol. Neurosurg. Psychiatr. 79 (6): 725–8. doi:10.1136/jnnp.2007.133025. PMID 18245139.

[88] Heil SG, Hogeveen M, Kluijtmans LA, et al. (2007). "Marfanoid features in a child with combined methylmalonic aciduria andhomocystinuria (CblC type)". J. Inherit. Metab. Dis. 30 (5): 811. doi:10.1007/s10545-007-0546-6. PMID 17768669.

[89] Tsai AC et al. (2007). "Late-onset combined homocystinuria and methylmalonic aciduria (cblC) and neuropsychiatric disturbance". Am. J.Med. Genet. A 143 (20): 2430–4. doi:10.1002/ajmg.a.31932. PMID 17853453.

[90] (http:/ / www. efsa. europa. eu/ EFSA/ efsa_locale-1178620753812_1211902125049. htm) safety of non-cyanocobalamin forms of B12

External links• Vitamin B12 Fact Sheet (http:/ / ods. od. nih. gov/ factsheets/ vitaminb12. asp) from the U.S. National Institutes

of Health• Jane Higdon, " Vitamin B12 (http:/ / lpi. oregonstate. edu/ infocenter/ vitamins/ vitaminB12/ )", Micronutrient

Information Center, Linus Pauling Institute, Oregon State University• Vitamin B12 (http:/ / www. nlm. nih. gov/ medlineplus/ druginfo/ natural/ patient-vitaminB12. html). Medline

Plus (National Library of Medicine). Part of it was used for this article (US Government public domain), speciallyfor drug and other interactions.

• Vitamin B12 deficiency (http:/ / www. aafp. org/ afp/ 20030301/ 979. html) article in American Family Physicianjournal

• Cyanocobalamin (http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2011/ MB_cgi?mode=& term=Cyanocobalamin) at theUS National Library of Medicine Medical Subject Headings (MeSH)

Article Sources and Contributors 17

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