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Vitamin B12

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(Redirected fromCobalamin)
This article is about the family of vitamers. For individual forms, seehydroxocobalamin,cyanocobalamin,methylcobalamin,andadenosylcobalamin.
"B12" and "Cbl" redirect here. For other uses of B12, seeB12 (disambiguation).For the musical group, seeCarbon Based Lifeforms.

Vitamin B12
Generalskeletal formulaof cobalamins
Stick modelofcyanocobalamin(R = CN) based on the crystal structure[1]
Clinical data
Other namesVitamin B12, vitamin B-12, cobalamin
AHFS/Drugs.comMonograph
MedlinePlusa605007
License data
Routes of
administration		By mouth,sublingual,intravenous(IV),intramuscular(IM), intranasal
ATC code
Legal status
Legal status
Pharmacokineticdata
BioavailabilityReadily absorbed in distal half of the ileum.
Protein bindingVery high to specifictranscobalaminsplasma proteins.
Binding ofhydroxocobalaminis slightly higher than cyanocobalamin.
MetabolismLiver
Eliminationhalf-lifeApproximately 6 days
(400 days in the liver).
ExcretionKidney
Identifiers
  • α-(5,6-Dimethylbenzimidazolyl)cobamidcyanide
CAS Number
PubChemCID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC63H88CoN14O14P
Molar mass1355.388g·mol−1
3D model (JSmol)
  • NC(=O)C[C@@]8(C)[C@H](CCC(N)=O)C=2/N=C8/C(/C)=C1/[C@@H](CCC(N)=O)[C@](C)(CC(N)=O)[C@@](C)(N1[Co+]C#N)[C@@H]7/N=C(C(\C)=C3/N=C(/C=2)C(C)(C)[C@@H]3CCC(N)=O)[C@](C)(CCC(=O)NCC(C)OP([O-])(=O)O[C@@H]6[C@@H](CO)O[C@H](n5cnc4cc(C)c(C)cc45)[C@@H]6O)[C@H]7CC(N)=O
  • InChI=1S/C62H90N13O14P.CN.Co/c1-29-20-39-40(21-30(29)2)75(28-70-39)57-52(84)53(41(27-76)87-57)89-90(85,86)88-31(3)26-69-49(83)18-19-59(8)37(22-46(66)80)56-62(11)61(10,25-48(68)82)36(14-17-45(65)79)51(74-62)33(5)55-60(9,24-47(67)81)34(12-15-43(63)77)38(71-55)23-42-58(6,7)35(13-16-44(64)78)50(72–42)32(4)54(59)73–56;1–2;/h20-21,23,28,31,34-37,41,52-53,56-57,76,84H,12-19,22,24-27H2,1-11H3,(H15,63,64,65,66,67,68,69,71,72,73,74,77,78,79,80,81,82,83,85,86);;/q;;+2/p-2/t31?,34-,35-,36-,37+,41-,52-,53-,56-,57+,59-,60+,61+,62+;;/m1../s1checkY
  • Key:RMRCNWBMXRMIRW-WYVZQNDMSA-LcheckY

Vitamin B12,also known ascobalamin,is a water-solublevitamininvolved inmetabolism.[2]It is one of eightB vitamins.It is required by animals, which use it as acofactorinDNA synthesis,and in bothfatty acidandamino acid metabolism.[3]It is important in the normal functioning of thenervous systemvia its role in thesynthesis of myelin,and in thecirculatory systemin the maturation ofred blood cellsin thebone marrow.[2][4]Plants do not need cobalamin and carry out the reactions with enzymes that are not dependent on it.[5]

Vitamin B12is the most chemically complex of all vitamins,[6]and for humans the only vitamin that must be sourced from animal-derived foods or supplements.[2][7]Only somearchaeaandbacteriacan synthesize vitamin B12.[8]Vitamin B12deficiency is a widespread condition that is particularly prevalent in populations with low consumption of animal foods. This can be due to a variety of reasons, such as low socioeconomic status, ethical considerations, or lifestyle choices such asveganism.[9]

Foods containing vitamin B12include meat,shellfish,liver,fish,poultry,eggs,anddairy products.[2]Manybreakfast cerealsarefortifiedwith the vitamin.[2]Supplementsand medications are available to treat and preventvitamin B12deficiency.[2]They are usually taken by mouth, but for the treatment of deficiency may also be given as anintramuscular injection.[2][6]

Vitamin B12deficiencies have a greater effect on young children, pregnant and elderly people, and are more common in middle and lower developed countries due to malnutrition.[10]The most common cause of vitamin B12deficiency in developed countries isimpaired absorptiondue to a loss ofgastric intrinsic factor(IF) which must be bound to a food-source of B12in order for absorption to occur.[11]A second major cause is an age-related decline instomach acidproduction (achlorhydria), because acid exposure frees protein-bound vitamin.[12]For the same reason, people on long-term antacid therapy, usingproton-pump inhibitors,H2blockersor other antacids are at increased risk.[13]

The diets of vegetarians and vegans may not provide sufficient B12unless a dietary supplement is taken.[2]A deficiency may be characterized by limbneuropathyor a blood disorder calledpernicious anemia,a type of anemiain which red blood cells become abnormally large.[2]This can result infatigue,decreased ability to think, lightheadedness, shortness of breath, frequentinfections,poor appetite,numbnessin the hands and feet, depression, memory loss, confusion,difficulty walking,blurred vision,irreversible nerve damage, and many others.[14]If left untreated in infants, deficiency may lead to neurological damage and anemia.[2]Folatelevels in the individual may affect the course of pathological changes and symptomatology of vitamin B12deficiency. Vitamin B12deficiency in pregnant women is strongly associated with an increased risk of spontaneous abortion, congenital malformations such as neural tube defects, problems with brain development growth in the unborn child.[10]

Vitamin B12was discovered as a result of pernicious anemia, anautoimmune disorderin which the blood has a lower than normal number of red blood cells, due to a deficiency of vitamin B12.[5][15]The ability to absorb the vitamin declines with age, especially in people over 60.[16]

Definition[edit]

Vitamin B12is acoordination complexofcobalt,which occupies the center of acorrinligand and is further bound to abenzimidazoleligand and adenosyl group.[17]A number of related species are known and these behave similarly, in particular all function as vitamins. This collection of compounds is sometimes referred to as "cobalamins". These chemical compounds have a similar molecular structure, each of which shows vitamin activity in a vitamin-deficient biological system, they are referred to asvitamers.The vitamin activity is as acoenzyme,meaning that its presence is required for some enzyme-catalyzed reactions.[12][18]

Cyanocobalamin is a manufactured form of B12.Bacterial fermentation creates AdoB12and MeB12,which are converted to cyanocobalamin by the addition of potassium cyanide in the presence of sodium nitrite and heat. Once consumed, cyanocobalamin is converted to the biologically active AdoB12and MeB12.The two bioactive forms of vitaminB
12aremethylcobalaminincytosolandadenosylcobalamininmitochondria.

Cyanocobalamin is the most common form used in dietary supplements andfood fortificationbecause cyanide stabilizes the molecule against degradation. Methylcobalamin is also offered as a dietary supplement.[12]There is no advantage to the use of adenosylcobalamin or methylcobalamin forms for the treatment of vitamin B12deficiency.[19][20][4]

Hydroxocobalamincan be injected intramuscularly to treat vitamin B12deficiency. It can also be injected intravenously for the purpose of treating cyanide poisoning, as the hydroxyl group is displaced by cyanide, creating a non-toxic cyanocobalamin that is excreted in urine.

"Pseudovitamin B12"refers to compounds that arecorrinoidswith a structure similar to the vitamin but without vitamin activity.[21]Pseudovitamin B12is the majority corrinoid inspirulina,an algal health food sometimes erroneously claimed as having this vitamin activity.[22]

Deficiency[edit]

Main article:Vitamin B12deficiency

Vitamin B12deficiency can potentially cause severe and irreversible damage, especially to the brain and nervous system.[6][23]Deficiency at levels only slightly lower than normal can cause a range of symptoms such asfatigue,feeling weak,lightheadedness,dizziness,breathlessness, headaches,mouth ulcers,upset stomach, decreased appetite, difficulty walking (staggering balance problems),[14][24]muscle weakness,depression,poormemory,poor reflexes, confusion, and pale skin,feeling abnormal sensations,among others, especially in people over age 60.[6][14][25]Vitamin B12deficiency can also cause symptoms ofmaniaandpsychosis.[26][27]Among other problems, weakened immunity, reduced fertility and interruption of blood circulation in women may occur.[28]

The main type ofvitamin B12 deficiencyanemia ispernicious anemia,[29]characterized by atriad of symptoms:

  1. Anemiawith bone marrow promegaloblastosis (megaloblastic anemia). This is due to the inhibition ofDNA synthesis(specificallypurinesandthymidine).
  2. Gastrointestinal symptoms: alteration in bowel motility, such as milddiarrheaorconstipation,and loss of bladder or bowel control.[30]These are thought to be due to defective DNA synthesis inhibiting replication in tissue sites with a high turnover of cells. This may also be due to theautoimmuneattack on theparietal cellsof the stomach in pernicious anemia. There is an association withgastric antral vascular ectasia(which can be referred to as watermelon stomach), and pernicious anemia.[31]
  3. Neurological symptoms: sensory or motor deficiencies (absent reflexes, diminished vibration or soft touch sensation) andsubacute combined degeneration of the spinal cord.[32]Deficiency symptoms in children includedevelopmental delay,regression,irritability,involuntary movementsandhypotonia.[33]

Vitamin B12deficiency is most commonly caused by malabsorption, but can also result from low intake, immune gastritis, low presence of binding proteins, or use of certain medications.[6]Vegans—people who choose to not consume any animal-sourced foods—are at risk because plant-sourced foods do not contain the vitamin in sufficient amounts to prevent vitamin deficiency.[34]Vegetarians—people who consume animal byproducts such as dairy products and eggs, but not the flesh of any animal—are also at risk. Vitamin B12deficiency has been observed in between 40% and 80% of the vegetarian population who do not also take a vitamin B12supplement or consume vitamin-fortified food.[35]In Hong Kong and India, vitamin B12deficiency has been found in roughly 80% of the vegan population. As with vegetarians, vegans can avoid this by consuming a dietary supplement or eating B12fortified food such as cereal, plant-based milks, andnutritional yeastas a regular part of their diet.[36]The elderly are at increased risk because they tend to produce lessstomach acidas they age, a condition known asachlorhydria,thereby increasing their probability of B12deficiency due to reduced absorption.[2]

Nitrous oxide overdose or overuse converts the active monovalent form of vitamin B12 to the inactive bivalent form.[37]

Pregnancy, lactation and early childhood[edit]

The U.S.Recommended Dietary Allowance (RDA)for pregnancy is2.6microgramsper day (μg/d),for lactation2.8 μg/d.Determination of these values was based on an RDA of2.4 μg/dfor non-pregnant women, plus what will be transferred to the fetus during pregnancy and what will be delivered in breast milk.[12][38]: 972 However, looking at the same scientific evidence, theEuropean Food Safety Authority(EFSA) sets adequate intake (AI) at4.5 μg/dfor pregnancy and5.0 μg/dfor lactation.[39]Low maternal vitamin B12,defined as serum concentration less than 148 pmol/L, increases the risk of miscarriage, preterm birth and newborn low birth weight.[40][38]During pregnancy theplacentaconcentrates B12,so that newborn infants have a higher serum concentration than their mothers.[12]As it is recently absorbed vitamin content that more effectively reaches the placenta, the vitamin consumed by the mother-to-be is more important than that contained in her liver tissue.[12][41]

Women who consume little animal-sourced food, or who are vegetarian or vegan, are at higher risk of becoming vitamin depleted during pregnancy than those who consume more animal products. This depletion can lead to anemia, and also an increased risk that their breastfed infants become vitamin deficient.[41][38]Vitamin B12is not one of the supplements recommended by the World Health Organization for healthy women who are pregnant,[10]however vitamin B12is often suggested during pregnancy in a multivitamin along with folic acid[42][43]especially for pregnant mothers who follow a vegetarian or vegan diet.[44]

Low vitamin concentrations in human milk occur in families with low socioeconomic status or low consumption of animal products.[38]: 971, 973 Only a few countries, primarily in Africa, have mandatory food fortification programs for either wheat flour or maize flour; India has a voluntary fortification program.[45]What the nursing mother consumes is more important than her liver tissue content, as it is recently absorbed vitamin that more effectively reaches breast milk.[38]: 973 Breast milk B12decreases over months of nursing in both well-nourished and vitamin-deficient mothers.[38]: 973–974 Exclusive or near-exclusive breastfeeding beyond six months is a strong indicator of low serum vitamin status in nursing infants. This is especially true when the vitamin status was poor during the pregnancy and if the early-introduced foods fed to the still breastfeeding infant are vegan.[38]: 974–975 

Risk of deficiency persists if the post-weaning diet is low in animal products.[38]: 974–975 Signs of low vitamin levels in infants and young children can include anemia, poor physical growth and neurodevelopmental delays.[38]: 975 Children diagnosed with low serum B12can be treated with intramuscular injections, then transitioned to an oral dietary supplement.[38]: 976 

Gastric bypass surgery[edit]

Various methods of gastric bypass or gastric restriction surgery are used to treat morbid obesity. Roux-en-Y gastric bypass surgery (RYGB) but not sleeve gastric bypass surgery or gastric banding, increases the risk of vitamin B12deficiency and requires preventive post-operative treatment with either injected or high-dose oral supplementation.[46][47][48]For post-operative oral supplementation,1000 μg/dmay be needed to prevent vitamin deficiency.[48]

Diagnosis[edit]

According to one review: "At present, no 'gold standard' test exists for the diagnosis of vitamin B12deficiency and as a consequence the diagnosis requires consideration of both the clinical state of the patient and the results of investigations. "[49]The vitamin deficiency is typically suspected when a routine complete blood count shows anemia with an elevatedmean corpuscular volume(MCV). In addition, on theperipheral blood smear,macrocytesand hypersegmentedpolymorphonuclear leukocytesmay be seen. Diagnosis is supported based on vitamin B12blood levels below 150–180pmol/L(200–250pg/mL) in adults.[50]However, serum values can be maintained while tissue B12stores are becoming depleted. Therefore, serum B12values above the cut-off point of deficiency do not necessarily confirm adequate B12status.[2]For this reason, elevated serumhomocysteineover 15 micromol/L andmethylmalonic acid(MMA) over 0.271 micromol/L are considered better indicators of B12deficiency, rather than relying only on the concentration of B12in blood.[2]However, elevated MMA is not conclusive, as it is seen in people with B12deficiency, but also in elderly people who have renal insufficiency,[27]and elevated homocysteine is not conclusive, as it is also seen in people with folate deficiency.[51]In addition, elevated methylmalonic acid levels may also be related to metabolic disorders such asmethylmalonic acidemia.[52]If nervous system damage is present and blood testing is inconclusive, alumbar puncturemay be carried out to measurecerebrospinal fluidB12levels.[53]

Serumhaptocorrinbinds 80-90% of circulating B12,rendering it unavailable for cellular delivery bytranscobalamin II.This is conjectured to be a circulating storage function.[54]Several serious, even life-threatening diseases cause elevated serum HC, measured as abnormally high serum vitamin B12,while at the same time potentially manifesting as a symptomatic vitamin deficiency because of insufficient vitamin bound to transcobalamin II which transfers the vitamin to cells.[55]

Medical uses[edit]

A vitamin B12solution (hydroxocobalamin) in a multi-dose bottle, with a single dose drawn up into a syringe for injection. Preparations are usually bright red.

Treatment of deficiency[edit]

Severe vitamin B12deficiency is initially corrected with daily intramuscular injections of1000 μgof the vitamin, followed by maintenance via monthly injections of the same amount or daily oral dosing of1000 μg.The daily dose is far in excess of the vitamin requirement because the normal transporter protein mediated absorption is absent, leaving only very inefficient intestinal passive absorption.[56][57]Injection side effects include skin rash, itching, chills, fever, hot flushes, nausea and dizziness. Oral maintenance treatment avoids this problem and significantly reduces cost of treatment.[56][57]

Cyanide poisoning[edit]

Forcyanidepoisoning, a large amount of hydroxocobalamin may be givenintravenouslyand sometimes in combination withsodium thiosulfate.[58][59]The mechanism of action is straightforward: the hydroxycobalamin hydroxideligandis displaced by the toxic cyanide ion, and the resulting non-toxic cyanocobalamin is excreted inurine.[60]

Dietary recommendations[edit]

Some research shows that most people in the United States and the United Kingdom consume sufficient vitamin B12.[2][11]However, other research suggests that the proportion of people with low or marginal levels of vitamin B12is up to 40% in theWestern world.[2]Grain-based foods can befortifiedby having the vitamin added to them. Vitamin B12supplements are available as single or multivitamin tablets.Pharmaceuticalpreparations of vitamin B12may be given byintramuscular injection.[6][61]Since there are few non-animal sources of the vitamin,vegansare advised to consume adietary supplementor fortified foods for B12intake, or risk serious health consequences.[6]Children in some regions ofdeveloping countriesare at particular risk due to increased requirements during growth coupled with diets low in animal-sourced foods.

The USNational Academy of Medicineupdated estimated average requirements (EARs) and recommended dietary allowances (RDAs) for vitamin B12in 1998.[6]The EAR for vitamin B12for women and men ages 14 and up is 2.0μg/day; the RDA is2.4 μg/d.RDA is higher than EAR so as to identify amounts that will cover people with higher than average requirements. RDA for pregnancy equals 2.6μg/day. RDA for lactation equals2.8 μg/d.For infants up to 12 months the adequate intake (AI) is 0.4–0.5μg/day. (AIs are established when there is insufficient information to determine EARs and RDAs.) For children ages 1–13 years the RDA increases with age from 0.9 to 1.8μg/day. Because 10 to 30 percent of older people may be unable to effectively absorb vitamin B12naturally occurring in foods, it is advisable for those older than 50 years to meet their RDA mainly by consuming foods fortified with vitamin B12or a supplement containing vitamin B12.As for safety,tolerable upper intake levels(known as ULs) are set for vitamins and minerals when evidence is sufficient. In the case of vitamin B12there is no UL, as there is no human data for adverse effects from high doses. Collectively the EARs, RDAs, AIs and ULs are referred to asdietary reference intakes(DRIs).[12]

TheEuropean Food Safety Authority(EFSA) refers to the collective set of information as "dietary reference values", with population reference intake (PRI) instead of RDA, and average requirement instead of EAR. AI and UL are defined by EFSA the same as in the United States. For women and men over age 18 the adequate intake (AI) is set at 4.0μg/day. AI for pregnancy is 4.5 μg/day, for lactation 5.0μg/day. For children aged 1–14 years the AIs increase with age from 1.5 to 3.5μg/day. These AIs are higher than the U.S. RDAs.[39]The EFSA also reviewed the safety question and reached the same conclusion as in the United States—that there was not sufficient evidence to set a UL for vitamin B12.[62]

The Japan National Institute of Health and Nutrition set the RDA for people ages 12 and older at 2.4μg/day.[63]TheWorld Health Organizationalso uses 2.4μg/day as the adult recommended nutrient intake for this vitamin.[64]

For U.S. food and dietary supplement labeling purposes, the amount in a serving is expressed as a "percent of daily value" (%DV). For vitamin B12labeling purposes, 100% of the daily value was 6.0μg, but on May 27, 2016, it was revised downward to 2.4μg.[65][66]Compliance with the updated labeling regulations was required by 1 January 2020 for manufacturers withUS$10 million or more in annual food sales, and by 1 January 2021 for manufacturers with lower volume food sales.[67][68]A table of the old and new adult daily values is provided atReference Daily Intake.

Sources[edit]

Bacteria and archaea[edit]

Vitamin B12is produced in nature by certainbacteria,andarchaea.[69][70][71]It is synthesized by some bacteria in thegut microbiotain humans and other animals, but it has long been thought that humans cannot absorb this as it is made in thecolon,downstream from thesmall intestine,where the absorption of most nutrients occurs.[72]Ruminants,such as cows and sheep, are foregut fermenters, meaning that plant food undergoes microbial fermentation in therumenbefore entering the true stomach (abomasum), and thus they are absorbing vitamin B12produced by bacteria.[72][73]

Other mammalian species (examples:rabbits,pikas,beaver,guinea pigs) consume high-fibre plants which pass through the gastrointestinal tract and undergo bacterial fermentation in thececumandlarge intestine.In thishindgut fermentation,the material from the cecum is expelled as "cecotropes"and are re-ingested, a practice referred to ascecotrophy.Re-ingestion allows for absorption of nutrients made available by bacterial fermentation, and also of vitamins and other nutrients synthesized by the gut bacteria, including vitamin B12.[73]

Non-ruminant, non-hindgut herbivores may have an enlarged forestomach and/or small intestine to provide a place for bacterial fermentation and B-vitamin production, including B12.[73]For gut bacteria to produce vitamin B12,the animal must consume sufficient amounts ofcobalt.[74]Soil that is deficient in cobalt may result in B12deficiency, and B12injections or cobalt supplementation may be required for livestock.[75]

Animal-derived foods[edit]

Animals store vitamin B12from their diets in theirliversandmusclesand some pass the vitamin into theireggsandmilk.Meat, liver, eggs and milk are therefore sources of the vitamin for other animals, including humans.[61][2][76]For humans, thebioavailabilityfrom eggs is less than 9%, compared to 40% to 60% from fish, fowl and meat.[77]Insects are a source of B12for animals (including other insects and humans).[76][78]Animal-derived food sources with a high concentration of vitamin B12includeliverand otherorgan meatsfromlamb,veal,beef,andturkey;alsoshellfishandcrab meat.[6][61][79]

Plants and algae[edit]

There is some evidence that bacterial fermentation of plant foods and symbiotic relationships between algae and bacteria can provide vitamin B12.However, theAcademy of Nutrition and Dieteticsconsiders plant and algae sources "unreliable", stating thatvegansshould turn to fortified foods and supplements instead.[34]

Natural plant andalgaesources of vitamin B12includefermentedplant foods such astempeh[80][81]and seaweed-derived foods such asnoriandlaverbread.[82][83][84]Methylcobalamin has been identified inChlorella vulgaris.[85]Since only bacteria and some archea possess the genes and enzymes necessary to synthesize vitamin B12,plant and algae sources all obtain the vitamin secondarily from symbiosis with various species of bacteria,[5]or in the case of fermented plant foods, from bacterial fermentation.[80]

Fortified foods[edit]

Foods for which vitamin B12-fortified versions are available includebreakfast cereals,plant-derivedmilk substitutessuch assoy milkandoat milk,energy bars,andnutritional yeast.[79]The fortification ingredient is cyanocobalamin. Microbial fermentation yields adenosylcobalamin, which is then converted to cyanocobalamin by addition of potassium cyanide or thiocyanate in the presence of sodium nitrite and heat.[86]

As of 2019, nineteen countries require food fortification of wheat flour, maize flour or rice with vitamin B12.Most of these are in southeast Africa or Central America.[45]

Vegan advocacy organizations, among others, recommend that every vegan consume B12from either fortified foods or supplements.[6][36][87][88]

Supplements[edit]

A blister pack of 500 μg methylcobalamin tablets

Vitamin B12is included in multivitamin pills; in some countries grain-based foods such as bread and pasta are fortified with B12.In the US, non-prescription products can be purchased providing up to 5,000μg each, and it is a common ingredient inenergy drinksandenergy shots,usually at many times the recommended dietary allowance of B12.The vitamin can also be supplied on prescription and delivered via injection or other means.[2]

Sublingualmethylcobalamin,which contains nocyanide,is available in 5mg tablets. The metabolic fate and biological distribution of methylcobalamin are expected to be similar to that of other sources of vitamin B12in the diet.[89]The amount of cyanide in cyanocobalamin is generally not a concern, even in the 1,000μg dose, since the amount of cyanide there (20μg in a 1,000μg cyanocobalamin tablet) is less than the daily consumption of cyanide from food, and therefore cyanocobalamin is not considered a health risk.[89]

Intramuscular or intravenous injection[edit]

Injection ofhydroxycobalaminis often used if digestive absorption is impaired,[2]but this course of action may not be necessary with high-dose oral supplements (such as 0.5–1.0mg or more),[90][91]because with large quantities of the vitamin taken orally, even the 1% to 5% of free crystalline B12that is absorbed along the entire intestine by passive diffusion may be sufficient to provide a necessary amount.[92]

A person with cobalamin C disease (which results in combinedmethylmalonic aciduriaandhomocystinuria) may require treatment with intravenous or intramuscular hydroxocobalamin or transdermal B12,because oral cyanocobalamin is inadequate in the treatment of cobalamin C disease.[93]

Nanotechnologies used in vitamin B12supplementation[edit]

Conventional administration does not ensure specific distribution and controlled release of vitamin B12.Moreover, therapeutic protocols involving injection require health care people and commuting of patients to the hospital thus increasing the cost of the treatment and impairing the lifestyle of patients. Targeted delivery of vitamin B12is a major focus of modern prescriptions. For example, conveying the vitamin to the bone marrow and nerve cells would help myelin recovery. Currently, several nanocarriers strategies are being developed for improving vitamin B12delivery with the aim to simplify administration, reduce costs, improve pharmacokinetics, and ameliorate the quality of patients' lives.[94]

Pseudovitamin-B12[edit]

Pseudovitamin-B12refers to B12-like analogues that are biologically inactive in humans.[21]Most cyanobacteria, includingSpirulina,and some algae, such asPorphyratenera(used to make a dried seaweed food callednoriin Japan), have been found to contain mostly pseudovitamin-B12instead of biologically active B12.[22][95]These pseudo-vitamin compounds can be found in some types of shellfish,[21]in edible insects,[96]and at times as metabolic breakdown products of cyanocobalamin added to dietary supplements and fortified foods.[97]

Pseudovitamin-B12can show up as biologically active vitamin B12when a microbiological assay withLactobacillus delbrueckiisubsp. lactis is used, as the bacteria can utilize the pseudovitamin despite it being unavailable to humans. To get a reliable reading of B12content, more advanced techniques are available. One such technique involves pre-separation bysilica geland then assessment with B12-dependentE. colibacteria.[21]

A related concept isantivitaminB12,compounds (often synthetic B12analogues) that not only have no vitamin action, but also actively interfere with the activity of true vitamin B12.The design of these compounds mainly involve replacement of the metal ion withrhodium,nickel,orzinc;or the attachment of an inactive ligand such as 4-ethylphenyl. These compounds have the potential to be used for analyzing B12utilization pathways or even attacking B12-dependent pathogens.[98]

Drug interactions[edit]

H2-receptor antagonists and proton-pump inhibitors[edit]

Gastric acid is needed to release vitamin B12from protein for absorption. Reduced secretion ofgastric acidandpepsin,from the use ofH2blockerorproton-pump inhibitor(PPI) drugs, can reduce absorption of protein-bound (dietary) vitamin B12,although not of supplemental vitamin B12.H2-receptor antagonist examples includecimetidine,famotidine,nizatidine,andranitidine.PPIs examples includeomeprazole,lansoprazole,rabeprazole,pantoprazole,andesomeprazole.Clinically significant vitamin B12deficiency and megaloblastic anemia are unlikely, unless these drug therapies are prolonged for two or more years, or if in addition the person's dietary intake is below recommended levels. Symptomatic vitamin deficiency is more likely if the person is renderedachlorhydric(a complete absence of gastric acid secretion), which occurs more frequently with proton pump inhibitors than H2blockers.[99]

Metformin[edit]

Reduced serum levels of vitamin B12occur in up to 30% of people taking long-termanti-diabeticmetformin.[100][101]Deficiency does not develop if dietary intake of vitamin B12is adequate or prophylactic B12supplementation is given. If the deficiency is detected, metformin can be continued while the deficiency is corrected with B12supplements.[102]

Other drugs[edit]

Certain medications can decrease the absorption of orally consumed vitamin B12,includingcolchicine,extended-releasepotassiumproducts, and antibiotics such asgentamicin,neomycinandtobramycin.[103]Anti-seizure medicationsphenobarbital,pregabalin,primidoneandtopiramateare associated with lower than normal serum vitamin concentration. However, serum levels were higher in people prescribedvalproate.[104]In addition, certain drugs may interfere with laboratory tests for the vitamin, such asamoxicillin,erythromycin,methotrexateandpyrimethamine.[103]

Chemistry[edit]

Methylcobalamin (shown) is a form of vitamin B12.Physically it resembles the other forms of vitamin B12,occurring as dark red crystals that freely form cherry-colored transparent solutions in water.

Vitamin B12is the most chemically complex of all the vitamins.[6]The structure of B12is based on acorrinring, which is similar to theporphyrinring found inheme.The central metal ion iscobalt.As isolated as an air-stable solid and available commercially, cobalt in vitamin B12(cyanocobalamin and other vitamers) is present in its +3 oxidation state. Biochemically, the cobalt center can take part in both two-electron and one-electron reductive processes to access the "reduced" (B12r,+2 oxidation state) and "super-reduced" (B12s,+1 oxidation state) forms. The ability to shuttle between the +1, +2, and +3 oxidation states is responsible for the versatile chemistry of vitamin B12,allowing it to serve as a donor of deoxyadenosyl radical (radical alkyl source) and as a methyl cation equivalent (electrophilic alkyl source).[105]

Four of the six coordination sites are provided by the corrin ring, and a fifth by adimethylbenzimidazolegroup. The sixth coordination site, thereactive center,is variable, being acyano group(–CN), ahydroxylgroup (–OH), amethylgroup (–CH3) or a 5′-deoxyadenosylgroup. Historically, the covalent carbon–cobalt bond is one of the first examples of carbon–metal bonds to be discovered in biology. Thehydrogenasesand, by necessity, enzymes associated with cobalt utilization, involve metal–carbon bonds.[106]Animals have the ability to convert cyanocobalamin and hydroxocobalamin to the bioactive forms adenosylcobalamin and methylcobalamin by means of enzymatically replacing the cyano or hydroxyl groups.

The structures of the four most common vitamers of cobalamin, together with some synonyms. The structure of the 5'-deoxyadenosyl group, which forms the R group of adenosylcobalamin is also shown.

Methods for the analysis of vitamin B12in food[edit]

Several methods have been used to determine the vitamin B12content in foods including microbiological assays, chemiluminescence assays, polarographic, spectrophotometric and high-performance liquid chromatography processes.[107]The microbiological assay has been the most commonly used assay technique for foods, utilizing certain vitamin B12-requiring microorganisms, such asLactobacillus delbrueckiisubsp.lactisATCC7830.[77]However, it is no longer the reference method due to the high measurement uncertainty of vitamin B12.[108]

Furthermore, this assay requires overnight incubation and may give false results if any inactive vitamin B12analogues are present in the foods.[109]Currently, radioisotope dilution assay (RIDA) with labelled vitamin B12and hog IF (pigs) have been used to determine vitamin B12content in food.[77]Previous reports have suggested that the RIDA method is able to detect higher concentrations of vitamin B12in foods compared to the microbiological assay method.[77][107]

Biochemistry[edit]

Coenzyme function[edit]

Vitamin B12functions as acoenzyme,meaning that its presence is required in some enzyme-catalyzed reactions.[12][18]Listed here are the three classes of enzymes that sometimes require B12to function (in animals):

  1. Isomerases
    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. These use the adoB12(adenosylcobalamin) form of the vitamin.[110]
  2. Methyltransferases
    Methyl (–CH3) group transfers between two molecules. These use the MeB12(methylcobalamin) form of the vitamin.[111]
  3. Dehalogenases
    Some species of anaerobic bacteria synthesize B12-dependent dehalogenases, which have potential commercial applications for degrading chlorinated pollutants. The microorganisms may either be capable ofde novocorrinoid biosynthesis or are dependent on exogenous vitamin B12.[112][113]

In humans, two major coenzyme B12-dependent enzyme families corresponding to the first two reaction types, are known. These are typified by the following two enzymes:

Simplified schematic diagram of the folate methionine cycle. Methionine synthase transfers the methyl group to the vitamin and then transfers the methyl group to homocysteine, converting that to methionine.

Methylmalonyl coenzyme A mutase(MUT) is an isomerase enzyme which uses the AdoB12form and reaction type 1 to convertL-methylmalonyl-CoAtosuccinyl-CoA,an important step in the catabolic breakdown of someamino acidsinto succinyl-CoA, which then enters energy production via thecitric acid cycle.[110]This functionality is lost invitamin B12deficiency,and can be measured clinically as an increased serummethylmalonic acid(MMA) concentration. The MUT function is necessary for propermyelinsynthesis.[4]Based on animal research, it is thought that the increased methylmalonyl-CoA hydrolyzes to form methylmalonate (methylmalonic acid), a neurotoxic dicarboxylic acid, causing neurological deterioration.[114]

Methionine synthase,coded byMTRgene, is a methyltransferase enzyme which uses the MeB12and reaction type 2 to transfer a methyl group from5-methyltetrahydrofolatetohomocysteine,thereby generatingtetrahydrofolate(THF) andmethionine.[111]This functionality is lost invitamin B12deficiency,resulting in an increasedhomocysteinelevel and the trapping offolateas 5-methyl-tetrahydrofolate, from which THF (the active form of folate) cannot be recovered. THF plays an important role in DNA synthesis, so reduced availability of THF results in ineffective production of cells with rapid turnover, in particular red blood cells, and also intestinal wall cells which are responsible for absorption. THF may be regenerated via MTR or may be obtained from fresh folate in the diet. Thus all of the DNA synthetic effects of B12deficiency, including themegaloblastic anemiaofpernicious anemia,resolve if sufficient dietary folate is present. Thus the best-known "function" of B12(that which is involved with DNA synthesis, cell-division, and anemia) is actually afacultativefunction which is mediated by B12-conservation of an active form of folate which is needed for efficient DNA production.[111]Other cobalamin-requiring methyltransferase enzymes are also known in bacteria, such as Me-H4-MPT, coenzyme M methyltransferase.[115]

Physiology[edit]

Absorption[edit]

Vitamin B12is absorbed by a B12-specific transport proteins or via passive diffusion.[12]Transport-mediated absorption and tissue delivery is a complex process involving three transport proteins:haptocorrin(HC),intrinsic factor(IF) andtranscobalamin II(TC2), and respective membrane receptor proteins. HC is present in saliva. As vitamin-containing food is digested byhydrochloric acidandpepsinsecreted into the stomach, HC binds the vitamin and protected it from acidic degradation.[12][116]Upon leaving the stomach the hydrochloric acid of thechymeis neutralized in theduodenumbybicarbonate,[117]and pancreatic proteases release the vitamin from HC, making it available to be bound by IF, which is a protein secreted by gastricparietal cellsin response to the presence of food in the stomach. IF delivers the vitamin to receptor proteinscubilinandamnionless,which together form thecubamreceptor in the distalileum.The receptor is specific to the IF-B12complex, and so will not bind to any vitamin content that is not bound to IF.[12][116]

Investigations into the intestinal absorption of B12confirm that the upper limit of absorption per single oral dose is about 1.5μg, with 50% efficiency. In contrast, the passive diffusion process of B12absorption — normally a very small portion of total absorption of the vitamin from food consumption — may exceed the haptocorrin- and IF-mediated absorption when oral doses of B12are very large, with roughly 1% efficiency. Thus, dietary supplement B12supplementation at 500 to 1000μg per day allowspernicious anemiaand certain other defects in B12absorption to be treated with daily oral megadoses of B12without any correction of the underlying absorption defects.[116]

After the IF/B12complex binds to cubam the complex is disassociated and the free vitamin is transported into theportal circulation.The vitamin is then transferred to TC2, which serves as the circulating plasma transporter, Hereditary defects in production of TC2 and its receptor may produce functional deficiencies in B12and infantilemegaloblastic anemia,and abnormal B12related biochemistry, even in some cases with normal blood B12levels. For the vitamin to serve inside cells, the TC2-B12complex must bind to a cell receptor protein and beendocytosed.TC2 is degraded within alysosome,and free B12is released into the cytoplasm, where it is transformed into the bioactive coenzyme by cellular enzymes.[116][118]

Malabsorption[edit]

Antaciddrugs that neutralize stomach acid and drugs that block acid production (such asproton-pump inhibitors) will inhibit absorption of B12by preventing release from food in the stomach.[119]Other causes of B12 malabsorption includeintrinsic factordeficiency,pernicious anemia,bariatric surgerypancreatic insufficiency, obstructive jaundice, tropical sprue and celiac disease, and radiation enteritis of the distal ileum.[116]Age can be a factor. Elderly people are oftenachlorhydricdue to reduced stomach parietal cell function, and thus have an increased risk of B12deficiency.[120]

Storage and excretion[edit]

How fast B12levels change depends on the balance between how much B12is obtained from the diet, how much is secreted and how much is absorbed. The total amount of vitamin B12stored in the body is about 2–5mg in adults. Around 50% of this is stored in the liver. Approximately 0.1% of this is lost per day by secretions into the gut, as not all these secretions are reabsorbed.Bileis the main form of B12excretion; most of the B12secreted in the bile is recycled viaenterohepatic circulation.Excess B12beyond the blood's binding capacity is typically excreted in urine. Owing to the extremely efficient enterohepatic circulation of B12,the liver can store 3 to 5 years' worth of vitamin B12;therefore, nutritional deficiency of this vitamin is rare in adults in the absence of malabsorption disorders.[12]In the absence of intrinsic factor or distal ileum receptors, only months to a year of vitamin B12are stored.[121]

Cellular reprogramming[edit]

Vitamin B12through its involvement in one-carbon metabolism plays a key role incellular reprogrammingand tissue regeneration and epigenetic regulation. Cellular reprogramming is the process by which somatic cells can be converted to a pluripotent state. Vitamin B12levels affect the histone modificationH3K36me3,which suppresses illegitimate transcription outside ofgene promoters.Mice undergoing in vivo reprogramming were found to become depleted in B12and show signs ofmethioninestarvation while supplementing reprogramming mice and cells with B12increased reprogramming efficiency, indicating a cell-intrinsic effect.[122][123]

Synthesis[edit]

Biosynthesis[edit]

Main article:Cobalamin biosynthesis

Vitamin B12is derived from atetrapyrrolic structural frameworkcreated by the enzymesdeaminaseandcosynthetasewhich transformaminolevulinic acidviaporphobilinogenandhydroxymethylbilanetouroporphyrinogen III.The latter is the firstmacrocyclicintermediate common toheme,chlorophyll,sirohemeand B12itself.[124][125]Later steps, especially the incorporation of the additional methyl groups of its structure, were investigated using13Cmethyl-labelledS-adenosyl methionine.It was not until agenetically engineeredstrain ofPseudomonas denitrificanswas used, in which eight of the genes involved in the biosynthesis of the vitamin had beenoverexpressed,that the complete sequence ofmethylationand other steps could be determined, thus fully establishing all the intermediates in the pathway.[126][127]

Species from the followinggeneraand the following individual species are known to synthesize B12:Propionibacteriumshermanii,Pseudomonasdenitrificans,Streptomycesgriseus,Acetobacterium,Aerobacter,Agrobacterium,Alcaligenes,Azotobacter,Bacillus,Clostridium,Corynebacterium,Flavobacterium,Lactobacillus,Micromonospora,Mycobacterium,Nocardia,Proteus, Rhizobium,Salmonella,Serratia,StreptococcusandXanthomonas.[128][129]

Industrial[edit]

Industrial production of B12is achieved throughfermentationof selected microorganisms.[130]Streptomyces griseus,a bacterium once thought to be afungus,was the commercial source of vitamin B12for many years.[131]The speciesPseudomonas denitrificansandPropionibacterium freudenreichiisubsp.shermaniiare more commonly used today.[130]These are grown under special conditions to enhance yield.Rhone-Poulencimproved yield via genetic engineeringP. denitrificans.[132]Propionibacterium,the other commonly used bacteria, produce noexotoxinsorendotoxinsand are generally recognized as safe (have been grantedGRASstatus) by theFood and Drug Administrationof the United States.[133]

The total world production of vitamin B12in 2008 was 35,000 kg (77,175 lb).[134]

Laboratory[edit]

Main article:Vitamin B12total synthesis

The complete laboratorysynthesis of B12was achieved byRobert Burns Woodward[135]andAlbert Eschenmoserin 1972.[136][137]The work required the effort of 91 postdoctoral fellows (mostly at Harvard) and 12 PhD students (atETH Zurich) from 19 nations. The synthesis constitutes a formal total synthesis, since the research groups only prepared the known intermediate cobyric acid, whose chemical conversion to vitamin B12was previously reported. This synthesis of vitamin B12is of no practical consequence due to its length, taking 72 chemical steps and giving an overall chemical yield well under 0.01%.[138]Although there have been sporadic synthetic efforts since 1972,[137]the Eschenmoser–Woodward synthesis remains the only completed (formal) total synthesis.

History[edit]

Further information:Vitamin § History

Descriptions of deficiency effects[edit]

Between 1849 and 1887,Thomas Addisondescribed a case ofpernicious anemia,William Oslerand William Gardner first described a case of neuropathy, Hayem described large red cells in the peripheral blood in this condition, which he called "giant blood corpuscles" (now calledmacrocytes),Paul Ehrlichidentifiedmegaloblastsin the bone marrow, andLudwig Lichtheimdescribed a case ofmyelopathy.[139]

Identification of liver as an anti-anemia food[edit]

During the 1920s,George Whipplediscovered that ingesting large amounts of rawliverseemed to most rapidly cure the anemia of blood loss in dogs, and hypothesized that eating liver might treat pernicious anemia.[140]Edwin Cohnprepared a liver extract that was 50 to 100 times more potent in treating pernicious anemia than the natural liver products.William Castledemonstrated that gastric juice contained an "intrinsic factor" which when combined with meat ingestion resulted in absorption of the vitamin in this condition.[139]In 1934, George Whipple shared the 1934Nobel Prize in Physiology or MedicinewithWilliam P. MurphyandGeorge Minotfor discovery of an effective treatment for pernicious anemia using liver concentrate, later found to contain a large amount of vitamin B12.[139][141]

Identification of the active compound[edit]

While working at the Bureau of Dairy Industry, U.S. Department of Agriculture,Mary Shaw Shorbwas assigned work on the bacterial strainLactobacillus lactisDorner (LLD), which was used to make yogurt and other cultured dairy products. The culture medium for LLD required liver extract. Shorb knew that the same liver extract was used to treat pernicious anemia (her father-in-law had died from the disease), and concluded that LLD could be developed as an assay method to identify the active compound. While at the University of Maryland she received a small grant fromMerck,and in collaboration withKarl Folkersfrom that company, developed the LLD assay. This identified "LLD factor" as essential for the bacteria's growth.[142]Shorb, Folker andAlexander R. Todd,at theUniversity of Cambridge,used the LLD assay to extract the anti-pernicious anemia factor from liver extracts, purify it, and name it vitamin B12.[143]In 1955, Todd helped elucidate the structure of the vitamin. The completechemical structureof the molecule was determined byDorothy Hodgkinbased oncrystallographicdata and published in 1955[144]and 1956,[145]for which, and for other crystallographic analyses, she was awarded the Nobel Prize in Chemistry in 1964.[146]Hodgkin went on to decipher the structure ofinsulin.[146]

George Whipple, George Minot and William Murphy were awarded the Nobel Prize in 1934 for their work on the vitamin. Three other Nobel laureates, Alexander R. Todd (1957), Dorothy Hodgkin (1964) and Robert Burns Woodward (1965) made important contributions to its study.[147]

Nobel laureates for discoveries relating to vitamin B12

Commercial production[edit]

Industrial production of vitamin B12is achieved throughfermentationof selected microorganisms.[130]As noted above, the completely synthetic laboratory synthesis of B12 was achieved by Robert Burns Woodward and Albert Eschenmoser in 1972, though this process has no commercial potential, requiring more than 70 steps and having a yield well below 0.01%.[138]

Society and culture[edit]

In the 1970s, John A. Myers, a physician residing in Baltimore, developed a program of injecting vitamins and minerals intravenously for various medical conditions. The formula included1000 μgof cyanocobalamin. This came to be known as theMyers' cocktail.After his death in 1984, other physicians and naturopaths took up prescribing "intravenous micro-nutrient therapy" with unsubstantiated health claims for treating fatigue, low energy, stress, anxiety, migraine, depression, immunocompromised, promoting weight loss and more.[148]However, other than a report on case studies[148]there are no benefits confirmed in the scientific literature.[149]Healthcare practitioners at clinics and spas prescribe versions of these intravenous combination products, but also intramuscular injections of just vitamin B12.A Mayo Clinic review concluded that there is no solid evidence that vitamin B12injections provide an energy boost or aid weight loss.[150]

There is evidence that for elderly people, physicians often repeatedly prescribe and administer cyanocobalamin injections inappropriately, evidenced by the majority of subjects in one large study either having had normal serum concentrations or had not been tested prior to the injections.[151]

See also[edit]

Further reading[edit]

  • Gherasim C, Lofgren M, Banerjee R (May 2013)."Navigating the B(12) road: assimilation, delivery, and disorders of cobalamin".J. Biol. Chem.288(19): 13186–13193.doi:10.1074/jbc.R113.458810.PMC3650358.PMID23539619.

References[edit]

  1. ^Prieto T, Neuburger M, Spingler B, Zelder F (2016)."Inorganic Cyanide as Protecting Group in the Stereospecific Reconstitution of Vitamin B12from an Artificial Green Secocorrinoid "(PDF).Org. Lett.18(20): 5292–5295.doi:10.1021/acs.orglett.6b02611.PMID27726382.
  2. ^abcdefghijklmnopqrOffice of Dietary Supplements (6 April 2021)."Vitamin B12: Fact Sheet for Health Professionals".Bethesda, Maryland:US National Institutes of Health.Archivedfrom the original on 2021-10-08.Retrieved24 December2021.
  3. ^Yamada K (2013). "Cobalt: Its Role in Health and Disease". In Sigel A, Sigel H, Sigel RK (eds.).Interrelations between Essential Metal Ions and Human Diseases.Metal Ions in Life Sciences. Vol. 13. Springer. pp. 295–320.doi:10.1007/978-94-007-7500-8_9.ISBN978-94-007-7499-5.PMID24470095.
  4. ^abcCalderón-Ospina CA, Nava-Mesa MO (January 2020)."B Vitamins in the nervous system: Current knowledge of the biochemical modes of action and synergies of thiamine, pyridoxine, and cobalamin".CNS Neurosci Ther.26(1): 5–13.doi:10.1111/cns.13207.PMC6930825.PMID31490017.
  5. ^abcSmith AG (2019-09-21). "Plants need their vitamins too".Current Opinion in Plant Biology.10(3): 266–275.doi:10.1016/j.pbi.2007.04.009.PMID17434786.
  6. ^abcdefghijk"Vitamin B12".Micronutrient Information Center, Linus Pauling Institute, Oregon State University, Corvallis, OR. 4 June 2015.Archivedfrom the original on 29 October 2019.Retrieved5 April2019.
  7. ^Vincenti A, Bertuzzo L, Limitone A, D'Antona G, Cena H (June 2021)."Perspective: Practical Approach to Preventing Subclinical B12 Deficiency in Elderly Population".Nutrients.13(6): 1913.doi:10.3390/nu13061913.PMC8226782.PMID34199569.
  8. ^Watanabe F, Bito T (January 2018)."Vitamin B12 sources and microbial interaction".Exp Biol Med (Maywood).243(2): 148–158.doi:10.1177/1535370217746612.PMC5788147.PMID29216732.
  9. ^Obeid R, Heil SG, Verhoeven MM, van den Heuvel EG, de Groot LC, Eussen SJ (2019)."Vitamin B12 Intake From Animal Foods, Biomarkers, and Health Aspects".Front Nutr.6:93.doi:10.3389/fnut.2019.00093.PMC6611390.PMID31316992.
  10. ^abcFinkelstein JL, Fothergill A, Venkatramanan S, Layden AJ, Williams JL, Crider KS, et al. (Cochrane Pregnancy and Childbirth Group) (January 2024). "Vitamin B12 supplementation during pregnancy for maternal and child health outcomes".The Cochrane Database of Systematic Reviews.1(1): CD013823.doi:10.1002/14651858.CD013823.pub2.PMC10772977.PMID38189492.
  11. ^abStabler SP (2020). "Vitamin B12". In Marriott BP, Birt DF, Stallings VA, Yates AA (eds.).Present Knowledge in Nutrition, Eleventh Edition.London: Academic Press (Elsevier). pp. 257–272.ISBN978-0-323-66162-1.US survey data from the NHANES What We Eat in America 2013e16 cohort reported the median vitamin B12 consumption for all adult men of 5.1 mcg and women of 3.5 mcg.95b Using the Estimated Average Requirement (EAR) for adults for Vitamin B12 of 2 mcg,93 less than 3% of men and 8% of women in the United States had inadequate diets using this comparator. However, 11% of girls 14e18 years had intakes less than their EAR of 2.0 mcg.
  12. ^abcdefghijklInstitute of Medicine(1998)."Vitamin B12".Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6,Folate, Vitamin B12,Pantothenic Acid, Biotin, and Choline.Washington, DC: The National Academies Press. pp. 306–356.ISBN978-0-309-06554-2.RetrievedFebruary 7,2012.
  13. ^"Acid-Reflux Drugs Tied to Lower Levels of Vitamin B-12".WebMD.Archivedfrom the original on 2018-07-23.Retrieved2018-07-23.
  14. ^abc"Vitamin B12 Deficiency Anemia".www.hopkinsmedicine.org.8 August 2021.Retrieved2022-02-16.
  15. ^"Pernicious anemia: MedlinePlus Medical Encyclopedia".medlineplus.gov.Retrieved2022-01-06.
  16. ^Baik HW, Russell RM (2021-11-18). "Vitamin B12 deficiency in the elderly".Annual Review of Nutrition.19:357–377.doi:10.1146/annurev.nutr.19.1.357.PMID10448529.
  17. ^Butler P, Kräutler B (2006). "Biological Organometallic Chemistry of B12".Bioorganometallic Chemistry.Topics in Organometallic Chemistry. Vol. 17. pp. 1–55.doi:10.1007/3418_004.ISBN3-540-33047-X.
  18. ^abBanerjee R, Ragsdale SW (July 2003)."The many faces of vitamin B12: catalysis by cobalamin-dependent enzymes".Annual Review of Biochemistry.72:209–247.doi:10.1146/annurev.biochem.72.121801.161828.PMID14527323.S2CID37393683.
  19. ^Obeid R, Fedosov SN, Nexo E (July 2015)."Cobalamin coenzyme forms are not likely to be superior to cyano- and hydroxyl-cobalamin in prevention or treatment of cobalamin deficiency".Molecular Nutrition & Food Research.59(7): 1364–1372.doi:10.1002/mnfr.201500019.PMC4692085.PMID25820384.
  20. ^Paul C, Brady DM (February 2017)."Comparative Bioavailability and Utilization of Particular Forms of B12 Supplements With Potential to Mitigate B12-related Genetic Polymorphisms".Integr Med (Encinitas).16(1): 42–49.PMC5312744.PMID28223907.
  21. ^abcdWatanabe F, Bito T (September 2018). "Determination of Cobalamin and Related Compounds in Foods".J AOAC Int.101(5): 1308–1313.doi:10.5740/jaoacint.18-0045.PMID29669618.S2CID4978703.
  22. ^abWatanabe F, Katsura H, Takenaka S, Fujita T, Abe K, Tamura Y, et al. (November 1999). "Pseudovitamin B(12) is the predominant cobamide of an algal health food, spirulina tablets".J. Agric. Food Chem.47(11): 4736–4741.doi:10.1021/jf990541b.PMID10552882.
  23. ^van der Put NM, van Straaten HW, Trijbels FJ, Blom HJ (April 2001). "Folate, homocysteine and neural tube defects: an overview".Experimental Biology and Medicine.226(4): 243–270.doi:10.1177/153537020122600402.PMID11368417.S2CID29053617.
  24. ^Skerrett PJ (February 2019)."Vitamin B12 deficiency can be sneaky, harmful".Harvard Health Blog.Archivedfrom the original on 29 October 2019.Retrieved6 January2020.
  25. ^"Vitamin B12or folate deficiency anaemia – Symptoms ".National Health Service, England. 23 May 2019.Archivedfrom the original on 12 August 2017.Retrieved6 January2020.
  26. ^Masalha R, Chudakov B, Muhamad M, Rudoy I, Volkov I, Wirguin I (September 2001)."Cobalamin-responsive psychosis as the sole manifestation of vitamin B12 deficiency".The Israel Medical Association Journal.3(9): 701–703.PMID11574992.
  27. ^abLachner C, Steinle NI, Regenold WT (2012). "The neuropsychiatry of vitamin B12 deficiency in elderly patients".J Neuropsychiatry Clin Neurosci.24(1): 5–15.doi:10.1176/appi.neuropsych.11020052.PMID22450609.S2CID20350330.
  28. ^Bennett M (March 2001). "Vitamin B12 deficiency, infertility and recurrent fetal loss".The Journal of Reproductive Medicine.46(3): 209–212.PMID11304860.
  29. ^"What Is Pernicious Anemia?".NHLBI.April 1, 2011.Archivedfrom the original on 14 March 2016.Retrieved14 March2016.
  30. ^Briani C, Dalla Torre C, Citton V, Manara R, Pompanin S, Binotto G, et al. (November 2013)."Cobalamin Deficiency: Clinical Picture and Radiological Findings".Nutrients.5(11): 4521–4539.doi:10.3390/nu5114521.ISSN2072-6643.PMC3847746.PMID24248213.
  31. ^Amarapurka DN, Patel ND (September 2004)."Gastric Antral Vascular Ectasia (GAVE) Syndrome"(PDF).Journal of the Association of Physicians of India.52:757.Archived(PDF)from the original on 2016-03-04.
  32. ^Greenburg M (2010).Handbook of Neurosurgery 7th Edition.New York: Thieme Publishers. pp. 1187–1188.ISBN978-1-60406-326-4.
  33. ^Lerner NB (2016). "Vitamin B12 Deficiency". In Kliegman RM, Stanton B, St Geme J, Schor NF (eds.).Nelson Textbook of Pediatrics(20th ed.). Elsevier Health Sciences. pp. 2319–2326.ISBN978-1-4557-7566-8.
  34. ^abMelina V, Craig W, Levin S (December 2016). "Position of the Academy of Nutrition and Dietetics: Vegetarian Diets".Journal of the Academy of Nutrition and Dietetics.116(12): 1970–1980.doi:10.1016/j.jand.2016.09.025.PMID27886704.S2CID4984228.Fermented foods (such as tempeh), nori, spirulina, chlorella algae, and unfortified nutritional yeast cannot be relied upon as adequate or practical sources of B-12.39,40 Vegans must regularly consume reliable sources—meaning B-12 fortified foods or B-12 containing supplements—or they could become deficient, as shown in case studies of vegan infants, children, and adults.
  35. ^Pawlak R, Parrott SJ, Raj S, Cullum-Dugan D, Lucus D (February 2013)."How prevalent is vitamin B(12) deficiency among vegetarians?".Nutrition Reviews.71(2): 110–117.doi:10.1111/nure.12001.PMID23356638.
  36. ^abWoo KS, Kwok TC, Celermajer DS (August 2014)."Vegan diet, subnormal vitamin B-12 status and cardiovascular health".Nutrients.6(8): 3259–3273.doi:10.3390/nu6083259.PMC4145307.PMID25195560.
  37. ^Stockton L, Simonsen C, Seago S (2017)."Nitrous oxide–induced vitamin B12 deficiency".Proceedings (Baylor University. Medical Center).30(2): 171–172.doi:10.1080/08998280.2017.11929571.PMC5349816.PMID28405070.
  38. ^abcdefghijObeid R, Murphy M, Solé-Navais P, Yajnik C (November 2017)."Cobalamin Status from Pregnancy to Early Childhood: Lessons from Global Experience".Advances in Nutrition.8(6): 971–979.doi:10.3945/an.117.015628.PMC5683008.PMID29141978.
  39. ^ab"Overview on Dietary Reference Values for the EU population as derived by the EFSA Panel on Dietetic Products, Nutrition and Allergies"(PDF).2017.Archived(PDF)from the original on 2020-01-07.Retrieved2017-08-28.
  40. ^Rogne T, Tielemans MJ, Chong MF, Yajnik CS, Krishnaveni GV, Poston L, et al. (February 2017)."Associations of Maternal Vitamin B12 Concentration in Pregnancy With the Risks of Preterm Birth and Low Birth Weight: A Systematic Review and Meta-Analysis of Individual Participant Data".Am J Epidemiol.185(3): 212–223.doi:10.1093/aje/kww212.PMC5390862.PMID28108470.
  41. ^abSebastiani G, Herranz Barbero A, Borrás-Novell C, Alsina Casanova M, Aldecoa-Bilbao V, Andreu-Fernández V, et al. (March 2019)."The Effects of Vegetarian and Vegan Diet during Pregnancy on the Health of Mothers and Offspring".Nutrients.11(3): 557.doi:10.3390/nu11030557.PMC6470702.PMID30845641.
  42. ^Wilson RD, O'Connor DL (June 2022). "Guideline No. 427: Folic Acid and Multivitamin Supplementation for Prevention of Folic Acid-Sensitive Congenital Anomalies".Journal of Obstetrics and Gynaecology Canada.44(6): 707–719.e1.doi:10.1016/j.jogc.2022.04.004.PMID35691683.
  43. ^"Nutrition During Pregnancy".www.acog.org.Retrieved2024-01-15.
  44. ^"Pregnancy: Vegetarian Diet".myhealth.alberta.ca.Retrieved2024-01-15.
  45. ^ab"Map: Count of Nutrients In Fortification Standards".Global Fortification Data Exchange.Archivedfrom the original on 11 April 2019.Retrieved15 April2020.
  46. ^Weng TC, Chang CH, Dong YH, Chang YC, Chuang LM (July 2015)."Anaemia and related nutrient deficiencies after Roux-en-Y gastric bypass surgery: a systematic review and meta-analysis".BMJ Open.5(7): e006964.doi:10.1136/bmjopen-2014-006964.PMC4513480.PMID26185175.
  47. ^Majumder S, Soriano J, Louie Cruz A, Dasanu CA (2013). "Vitamin B12 deficiency in patients undergoing bariatric surgery: preventive strategies and key recommendations".Surg Obes Relat Dis.9(6): 1013–1019.doi:10.1016/j.soard.2013.04.017.PMID24091055.
  48. ^abMahawar KK, Reid A, Graham Y, Callejas-Diaz L, Parmar C, Carr WR, et al. (July 2018). "Oral Vitamin B12 Supplementation After Roux-en-Y Gastric Bypass: a Systematic Review".Obes Surg.28(7): 1916–1923.doi:10.1007/s11695-017-3102-y.PMID29318504.S2CID35209784.
  49. ^Shipton MJ, Thachil J (April 2015)."Vitamin B12 deficiency – A 21st century perspective".Clin Med (Lond).15(2): 145–150.doi:10.7861/clinmedicine.15-2-145.PMC4953733.PMID25824066.
  50. ^Devalia V, Hamilton MS, Molloy AM (August 2014)."Guidelines for the diagnosis and treatment of cobalamin and folate disorders".Br. J. Haematol.166(4): 496–513.doi:10.1111/bjh.12959.PMID24942828.S2CID5772424.
  51. ^Moretti R, Caruso P (January 2019)."The Controversial Role of Homocysteine in Neurology: From Labs to Clinical Practice".Int J Mol Sci.20(1): 231.doi:10.3390/ijms20010231.PMC6337226.PMID30626145.
  52. ^"Methylmalonic acidemia".Genetics Home Reference.US National Library of Medecine. October 2015.Retrieved10 July2022.
  53. ^Devalia V (Aug 2006)."Diagnosing vitamin B-12 deficiency on the basis of serum B-12 assay".BMJ.333(7564): 385–386.doi:10.1136/bmj.333.7564.385.PMC1550477.PMID16916826.
  54. ^McCorvie TJ, Ferreira D, Yue WW, Froese DS (May 2023). "The complex machinery of human cobalamin metabolism".J Inherit Metab Dis.46(3): 406–20.doi:10.1002/jimd.12593.PMID36680553.
  55. ^Ermens AA, Vlasveld LT, Lindemans J (November 2003). "Significance of elevated cobalamin (vitamin B12) levels in blood".Clin Biochem.36(8): 585–90.doi:10.1016/j.clinbiochem.2003.08.004.PMID14636871.
  56. ^abElangovan R, Baruteau J (September 2022)."Inherited and acquired vitamin B12 deficiencies: Which administration route to choose for supplementation?".Front Pharmacol.13:972468.doi:10.3389/fphar.2022.972468.PMC9559827.PMID36249776.
  57. ^abAndrès E, Zulfiqar AA, Serraj K, Vogel T, Kaltenbach G (September 2018)."Systematic review and pragmatic clinical approach to oral and nasal vitamin B12 (cobalamin) treatment in patients with vitamin B12 deficiency related to gastrointestinal disorders".J Clin Med.7(10): 304–17.doi:10.3390/jcm7100304.PMC6210286.PMID30261596.
  58. ^Hall AH, Rumack BH (1987). "Hydroxycobalamin/sodium thiosulfate as a cyanide antidote".The Journal of Emergency Medicine.5(2): 115–121.doi:10.1016/0736-4679(87)90074-6.PMID3295013.
  59. ^MacLennan L, Moiemen N (February 2015). "Management of cyanide toxicity in patients with burns".Burns.41(1): 18–24.doi:10.1016/j.burns.2014.06.001.PMID24994676.
  60. ^Dart RC (2006)."Hydroxocobalamin for acute cyanide poisoning: new data from preclinical and clinical studies; new results from the prehospital emergency setting".Clinical Toxicology.44(Suppl. 1): 1–3.doi:10.1080/15563650600811607.PMID16990188.
  61. ^abc"Foods highest in Vitamin B12(based on levels per 100-gram serving) ".Nutrition Data.Condé Nast, USDA National Nutrient Database, release SR-21. 2014.Archivedfrom the original on November 16, 2019.RetrievedFebruary 16,2017.
  62. ^"Tolerable Upper Intake Levels For Vitamins And Minerals"(PDF).European Food Safety Authority. 2006.Archived(PDF)from the original on 2019-10-15.Retrieved2016-03-12.
  63. ^"Dietary Reference Intakes for Japanese 2010: Water-Soluble Vitamins"Journal of Nutritional Science and Vitaminology2013(59):S67–S82.
  64. ^World Health Organization(2005). "Chapter 14: Vitamin B12".Vitamin and Mineral Requirements in Human Nutrition(2nd ed.). Geneva: World Health Organization. pp.279–287.hdl:10665/42716.ISBN978-92-4-154612-6.
  65. ^"Food Labeling: Revision of the Nutrition and Supplement Facts Labels"(PDF).Federal Register.May 27, 2016. p. 33982.Archived(PDF)from the original on August 8, 2016.RetrievedAugust 27,2017.
  66. ^"Daily Value Reference of the Dietary Supplement Label Database (DSLD)".Dietary Supplement Label Database (DSLD).Archived fromthe originalon 7 April 2020.Retrieved16 May2020.
  67. ^"Changes to the Nutrition Facts Label".U.S.Food and Drug Administration(FDA).27 May 2016.Retrieved16 May2020.Public DomainThis article incorporates text from this source, which is in thepublic domain.
  68. ^"Industry Resources on the Changes to the Nutrition Facts Label".U.S.Food and Drug Administration(FDA).21 December 2018.Retrieved16 May2020.Public DomainThis article incorporates text from this source, which is in thepublic domain.
  69. ^Fang H, Kang J, Zhang D (January 2017)."Microbial production of vitamin B12: a review and future perspectives".Microbial Cell Factories.16(1): 15.doi:10.1186/s12934-017-0631-y.PMC5282855.PMID28137297.
  70. ^Moore SJ, Warren MJ (June 2012)."The anaerobic biosynthesis of vitamin B12"(PDF).Biochemical Society Transactions.40(3): 581–586.doi:10.1042/BST20120066.PMID22616870.S2CID26057998.
  71. ^Graham RM, Deery E, Warren MJ (2009). "18: Vitamin B12:Biosynthesis of the Corrin Ring ". In Warren MJ,Smith(eds.).Tetrapyrroles Birth, Life and Death.New York: Springer-Verlag. p. 286.doi:10.1007/978-0-387-78518-9_18.ISBN978-0-387-78518-9.
  72. ^abGille D, Schmid A (February 2015)."Vitamin B12 in meat and dairy products".Nutrition Reviews.73(2): 106–115.doi:10.1093/nutrit/nuu011.PMID26024497.
  73. ^abcStevens CE, Hume ID (April 1998)."Contributions of microbes in vertebrate gastrointestinal tract to production and conservation of nutrients".Physiol. Rev.78(2): 393–427.doi:10.1152/physrev.1998.78.2.393.PMID9562034.S2CID103191.
  74. ^McDowell LR (2008).Vitamins in Animal and Human Nutrition(2nd ed.). Hoboken: John Wiley & Sons. pp. 525, 539.ISBN978-0-470-37668-3.Archivedfrom the original on 2017-09-08.Retrieved2017-01-17.
  75. ^Erickson A (September 3, 2019)."Cobalt deficiency in sheep and cattle".Department of Primary Industries and Regional Development.Government of Western Australia.Archivedfrom the original on 2015-11-11.Retrieved2020-04-18.
  76. ^abRooke J (October 30, 2013)."Do carnivores need Vitamin B12supplements? ".Baltimore Post Examiner.Archivedfrom the original on January 16, 2017.RetrievedJanuary 17,2017.
  77. ^abcdWatanabe F (November 2007). "Vitamin B12 sources and bioavailability".Experimental Biology and Medicine.232(10): 1266–1274.doi:10.3181/0703-MR-67.PMID17959839.S2CID14732788.
  78. ^Dossey AT (February 1, 2013)."Why Insects Should Be in Your Diet".The Scientist.Archivedfrom the original on November 11, 2017.RetrievedApril 18,2020.
  79. ^ab"Vitamin B-12 (μg)"(PDF).USDA National Nutrient Database for Standard Reference Release 28.27 October 2015.Archived(PDF)from the original on 26 January 2017.Retrieved6 January2020.
  80. ^abKeuth S, Bisping B (May 1994)."Vitamin B12 production by Citrobacter freundii or Klebsiella pneumoniae during tempeh fermentation and proof of enterotoxin absence by PCR".Applied and Environmental Microbiology.60(5): 1495–1499.Bibcode:1994ApEnM..60.1495K.doi:10.1128/AEM.60.5.1495-1499.1994.PMC201508.PMID8017933.
  81. ^Mo H, Kariluoto S, Piironen V, Zhu Y, Sanders MG, Vincken JP, et al. (December 2013)."Effect of soybean processing on content and bioaccessibility of folate, vitamin B12 and isoflavones in tofu and tempe".Food Chemistry.141(3): 2418–2425.doi:10.1016/j.foodchem.2013.05.017.PMID23870976.
  82. ^Watanabe F, Yabuta Y, Bito T, Teng F (May 2014)."Vitamin B₁₂-containing plant food sources for vegetarians".Nutrients.6(5): 1861–1873.doi:10.3390/nu6051861.PMC4042564.PMID24803097.
  83. ^Kwak CS, Lee MS, Lee HJ, Whang JY, Park SC (June 2010)."Dietary source of vitamin B(12) intake and vitamin B(12) status in female elderly Koreans aged 85 and older living in rural area".Nutrition Research and Practice.4(3): 229–234.doi:10.4162/nrp.2010.4.3.229.PMC2895704.PMID20607069.
  84. ^Kwak CS, Lee MS, Oh SI, Park SC (2010)."Discovery of novel sources of vitamin b(12) in traditional korean foods from nutritional surveys of centenarians".Current Gerontology and Geriatrics Research.2010:374897.doi:10.1155/2010/374897.PMC3062981.PMID21436999.
  85. ^Kumudha A, Selvakumar S, Dilshad P, Vaidyanathan G, Thakur MS, Sarada R (March 2015). "Methylcobalamin – a form of vitamin B12 identified and characterised in Chlorella vulgaris".Food Chemistry.170:316–320.doi:10.1016/j.foodchem.2014.08.035.PMID25306351.
  86. ^Martins JH, Barg H, Warren MJ, Jahn D (March 2002). "Microbial production of vitamin B12".Appl Microbiol Biotechnol.58(3): 275–285.doi:10.1007/s00253-001-0902-7.PMID11935176.S2CID22232461.
  87. ^Mangels R."Vitamin B12in the Vegan Diet ".Vegetarian Resource Group.Archivedfrom the original on December 19, 2012.RetrievedJanuary 17,2008.
  88. ^"Don't Vegetarians Have Trouble Getting Enough Vitamin B12?".Physicians Committee for Responsible Medicine.Archivedfrom the original on October 8, 2011.RetrievedJanuary 17,2008.
  89. ^abEuropean Food Safety Authority(September 25, 2008)."5′-deoxyadenosylcobalamin and methylcobalamin as sources for Vitamin B12added as a nutritional substance in food supplements: Scientific opinion of the Scientific Panel on Food Additives and Nutrient Sources added to food ".EFSA Journal.815(10): 1–21.doi:10.2903/j.efsa.2008.815."the metabolic fate and biological distribution of methylcobalamin and 5′-deoxyadenosylcobalamin are expected to be similar to that of other sources of vitamin B12in the diet ".
  90. ^Lane LA, Rojas-Fernandez C (July–August 2002). "Treatment of vitamin b(12)-deficiency anemia: oral versus parenteral therapy".The Annals of Pharmacotherapy.36(7–8): 1268–1272.doi:10.1345/aph.1A122.PMID12086562.S2CID919401.
  91. ^Butler CC, Vidal-Alaball J, Cannings-John R, McCaddon A, Hood K, Papaioannou A, et al. (June 2006)."Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency: a systematic review of randomized controlled trials".Family Practice.23(3): 279–285.CiteSeerX10.1.1.488.7931.doi:10.1093/fampra/cml008.PMID16585128.
  92. ^Arslan SA, Arslan I, Tirnaksiz F (March 2013). "Cobalamins and Methylcobalamin: Coenzyme of Vitamin B12".FABAD J. Pharm. Sci.38(3): 151–157.S2CID1929961.
  93. ^Thauvin-Robinet C, Roze E, Couvreur G, Horellou MH, Sedel F, Grabli D, et al. (June 2008). "The adolescent and adult form of cobalamin C disease: clinical and molecular spectrum".Journal of Neurology, Neurosurgery, and Psychiatry.79(6): 725–728.doi:10.1136/jnnp.2007.133025.PMID18245139.S2CID23493993.
  94. ^Fidaleo M, Tacconi S, Sbarigia C, Passeri D, Rossi M, Tata AM, et al. (March 2021)."Current Nanocarrier Strategies Improve Vitamin B12 Pharmacokinetics, Ameliorate Patients' Lives, and Reduce Costs".Nanomaterials.11(3): 743.doi:10.3390/nano11030743.PMC8001893.PMID33809596.
  95. ^Yamada K, Yamada Y, Fukuda M, Yamada S (November 1999). "Bioavailability of Dried Asakusanori (Porphyra tenera) as a Source of Cobalamin (Vitamin B12) ".International Journal for Vitamin and Nutrition Research.69(6): 412–418.doi:10.1024/0300-9831.69.6.412.PMID10642899.
  96. ^Schmidt A, Call LM, Macheiner L, Mayer HK (May 2019). "Determination of vitamin B12in four edible insect species by immunoaffinity and ultra-high performance liquid chromatography ".Food Chemistry.281:124–129.doi:10.1016/j.foodchem.2018.12.039.PMID30658738.S2CID58651702.
  97. ^Yamada K, Shimodaira M, Chida S, Yamada N, Matsushima N, Fukuda M, et al. (2008). "Degradation of vitamin B12 in dietary supplements".International Journal for Vitamin and Nutrition Research.78(4–5): 195–203.doi:10.1024/0300-9831.78.45.195.PMID19326342.
  98. ^Kräutler B (December 2020)."Antivitamins B12-Some Inaugural Milestones ".Chemistry: A European Journal.26(67): 15438–15445.doi:10.1002/chem.202003788.PMC7756841.PMID32956545.
  99. ^DeVault KR, Talley NJ (September 2009). "Insights into the future of gastric acid suppression".Nat Rev Gastroenterol Hepatol.6(9): 524–532.doi:10.1038/nrgastro.2009.125.PMID19713987.S2CID25413839.
  100. ^Ahmed MA (2016)."Metformin and Vitamin B12 Deficiency: Where Do We Stand?".Journal of Pharmacy & Pharmaceutical Sciences.19(3): 382–398.doi:10.18433/J3PK7P.hdl:2263/60716.PMID27806244.
  101. ^Gilligan MA (February 2002). "Metformin and vitamin B12 deficiency".Archives of Internal Medicine.162(4): 484–485.doi:10.1001/archinte.162.4.484.PMID11863489.
  102. ^Copp S (1 December 2007)."What effect does metformin have on vitamin B12levels? ".UK Medicines Information, NHS. Archived fromthe originalon September 27, 2007.
  103. ^ab"Vitamin B-12: Interactions".WebMD.Retrieved21 April2020.
  104. ^Linnebank M, Moskau S, Semmler A, Widman G, Stoffel-Wagner B, Weller M, et al. (February 2011)."Antiepileptic drugs interact with folate and vitamin B12 serum levels"(PDF).Ann. Neurol.69(2): 352–359.doi:10.1002/ana.22229.PMID21246600.S2CID7282489.
  105. ^Giedyk M, Goliszewska K, Gryko D (June 2015). "Vitamin B12 catalysed reactions".Chemical Society Reviews.44(11): 3391–3404.doi:10.1039/C5CS00165J.PMID25945462.
  106. ^Jaouen G, ed. (2006).Bioorganometallics: Biomolecules, Labeling, Medicine.Weinheim: Wiley-VCH. pp. 17–25.ISBN978-3-527-30990-0.
  107. ^abLawrance P (March 2015)."Vitamin B12: A review of analytical methods for use in food".LGC Limited.
  108. ^O'Leary F, Samman S (March 2010)."Vitamin B12 in Health and Disease".Nutrients.2(3): 299–316.doi:10.3390/nu2030299.ISSN2072-6643.PMC3257642.PMID22254022.
  109. ^Obeid R, ed. (2017-07-12).Vitamin B12.CRC Press.doi:10.1201/9781315119540.ISBN978-1-315-11954-0.
  110. ^abTakahashi-Iñiguez T, García-Hernandez E, Arreguín-Espinosa R, Flores ME (June 2012)."Role of vitamin B12 on methylmalonyl-CoA mutase activity".J Zhejiang Univ Sci B.13(6): 423–437.doi:10.1631/jzus.B1100329.PMC3370288.PMID22661206.
  111. ^abcFroese DS, Fowler B, Baumgartner MR (July 2019)."Vitamin B12, folate, and the methionine remethylation cycle-biochemistry, pathways, and regulation"(PDF).Journal of Inherited Metabolic Disease.42(4): 673–685.doi:10.1002/jimd.12009.PMID30693532.
  112. ^Reinhold A, Westermann M, Seifert J, von Bergen M, Schubert T, Diekert G (November 2012)."Impact of vitamin B12 on formation of the tetrachloroethene reductive dehalogenase in Desulfitobacterium hafniense strain Y51".Appl. Environ. Microbiol.78(22): 8025–8032.Bibcode:2012ApEnM..78.8025R.doi:10.1128/AEM.02173-12.PMC3485949.PMID22961902.
  113. ^Payne KA, Quezada CP, Fisher K, Dunstan MS, Collins FA, Sjuts H, et al. (January 2015)."Reductive dehalogenase structure suggests a mechanism for B12-dependent dehalogenation".Nature.517(7535): 513–516.Bibcode:2015Natur.517..513P.doi:10.1038/nature13901.PMC4968649.PMID25327251.
  114. ^Ballhausen D, Mittaz L, Boulat O, Bonafé L, Braissant O (December 2009). "Evidence for catabolic pathway of propionate metabolism in CNS: expression pattern of methylmalonyl-CoA mutase and propionyl-CoA carboxylase alpha-subunit in developing and adult rat brain".Neuroscience.164(2): 578–587.doi:10.1016/j.neuroscience.2009.08.028.PMID19699272.S2CID34612963.
  115. ^Marsh EN (1999). "Coenzyme B12 (cobalamin)-dependent enzymes".Essays Biochem.34:139–154.doi:10.1042/bse0340139.PMID10730193.
  116. ^abcdeGuéant JL, Guéant-Rodriguez RM, Alpers DH (2022). "Vitamin B12 absorption and malabsorption".Vitam Horm.Vitamins and Hormones.119:241–274.doi:10.1016/bs.vh.2022.01.016.ISBN978-0-323-99223-7.PMID35337622.
  117. ^Maton A, Hopkins J, McLaughlin CW, Johnson S, Warner MQ, LaHart D, et al. (1993).Human Biology and Health.Englewood Cliffs, New Jersey, USA: Prentice Hall.ISBN978-0-13-981176-0.
  118. ^Seetharam B, Li N (2000). "Transcobalamin II and its cell surface receptor".Vitam Horm.Vitamins & Hormones.59:337–66.doi:10.1016/s0083-6729(00)59012-8.ISBN978-0-12-709859-3.PMID10714245.
  119. ^Lam JR, Schneider JL, Zhao W, Corley DA (December 2013)."Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency".JAMA.310(22): 2435–42.doi:10.1001/jama.2013.280490.PMID24327038.
  120. ^Baik HW, Russell RM (1999). "Vitamin B12 deficiency in the elderly".Annual Review of Nutrition.19:357–77.doi:10.1146/annurev.nutr.19.1.357.PMID10448529.
  121. ^"Vitamin B12 Deficiency – Nutritional Disorders".MSD Manual Professional Edition.Retrieved2022-05-24.
  122. ^Kovatcheva M, Melendez E, Chondronasiou D, Pietrocola F, Bernad R, Caballe A, et al. (November 2023)."Vitamin B12is a limiting factor for induced cellular plasticity and tissue repair ".Nature Metabolism.5(11): 1911–1930.doi:10.1038/s42255-023-00916-6.PMC10663163.PMID37973897.
  123. ^Vílchez-Acosta A, Desdín-Micó G, Ocampo A (November 2023). "Vitamin B12emerges as key player during cellular reprogramming ".Nature Metabolism.5(11): 1844–1845.doi:10.1038/s42255-023-00917-5.PMID37973898.S2CID265273574.
  124. ^Battersby AR, Fookes CJ, Matcham GW, McDonald E (May 1980)."Biosynthesis of the pigments of life: formation of the macrocycle".Nature.285(5759): 17–21.Bibcode:1980Natur.285...17B.doi:10.1038/285017a0.PMID6769048.S2CID9070849.
  125. ^Frank S, Brindley AA, Deery E, Heathcote P, Lawrence AD, Leech HK, et al. (August 2005)."Anaerobic synthesis of vitamin B12: characterization of the early steps in the pathway"(PDF).Biochemical Society Transactions.33(Pt 4): 811–814.doi:10.1042/BST0330811.PMID16042604.
  126. ^Battersby AR(1993)."How Nature builds the pigments of life"(PDF).Pure and Applied Chemistry.65(6): 1113–1122.doi:10.1351/pac199365061113.S2CID83942303.Archived(PDF)from the original on 2018-07-24.Retrieved2020-02-20.
  127. ^Battersby A (2005). "Chapter 11: Discovering the wonder of how Nature builds its molecules". InArcher MD,Haley CD (eds.).The 1702 chair of chemistry at Cambridge: transformation and change.Cambridge University Press. pp. xvi, 257–282.ISBN0-521-82873-2.
  128. ^Perlman D (1959). "Microbial synthesis of cobamides".Advances in Applied Microbiology.1:87–122.doi:10.1016/S0065-2164(08)70476-3.ISBN978-0-12-002601-2.PMID13854292.
  129. ^Martens JH, Barg H, Warren MJ, Jahn D (March 2002). "Microbial production of vitamin B12".Applied Microbiology and Biotechnology.58(3): 275–285.doi:10.1007/s00253-001-0902-7.PMID11935176.S2CID22232461.
  130. ^abcFang H, Kang J, Zhang D (January 2017)."Microbial production of vitamin B12: a review and future perspectives".Microb. Cell Fact.16(1): 15.doi:10.1186/s12934-017-0631-y.PMC5282855.PMID28137297.
  131. ^Linnell JC, Matthews DM (February 1984)."Cobalamin metabolism and its clinical aspects"(PDF).Clinical Science.66(2): 113–121.doi:10.1042/cs0660113.PMID6420106.S2CID27191837.
  132. ^Piwowarek K, Lipińska E, Hać-Szymańczuk E, Kieliszek M, Ścibisz I (January 2018)."Propionibacterium spp.-source of propionic acid, vitamin B12, and other metabolites important for the industry".Appl. Microbiol. Biotechnol.102(2): 515–538.doi:10.1007/s00253-017-8616-7.PMC5756557.PMID29167919.
  133. ^Riaz M, Ansari ZA, Iqbal F, Akram M (2007)."Microbial production of vitamin B12by methanol utilizing strain ofPseudomonasspecies ".Pakistan Journal of Biochemistry & Molecular Biology.40:5–10.[permanent dead link]
  134. ^Zhang Y (January 26, 2009)."New round of price slashing in vitamin B12sector (Fine and Specialty) ".China Chemical Reporter.Archived fromthe originalon May 13, 2013.
  135. ^Khan AG, Eswaran SV (June 2003). "Woodward's synthesis of vitamin B12".Resonance.8(6): 8–16.doi:10.1007/BF02837864.S2CID120110443.
  136. ^Eschenmoser A, Wintner CE (June 1977). "Natural product synthesis and vitamin B12".Science.196(4297): 1410–1420.Bibcode:1977Sci...196.1410E.doi:10.1126/science.867037.PMID867037.
  137. ^abRiether D, Mulzer J (2003). "Total Synthesis of Cobyric Acid: Historical Development and Recent Synthetic Innovations".European Journal of Organic Chemistry.2003:30–45.doi:10.1002/1099-0690(200301)2003:1<30::AID-EJOC30>3.0.CO;2-I.
  138. ^ab"Synthesis of Cyanocobalamin by Robert B. Woodward (1973)".www.synarchive.com.Archivedfrom the original on 2018-02-16.Retrieved2018-02-15.
  139. ^abcGreer JP (2014).Wintrobe's Clinical Hematology Thirteenth Edition.Philadelphia, PA: Wolters Kluwer/Lippincott Williams & Wilkins.ISBN978-1-4511-7268-3.Chapter 36: Megaloblastic anemias: disorders of impaired DNA synthesis by Ralph Carmel
  140. ^"George H. Whipple – Biographical".www.nobelprize.org.Archivedfrom the original on 2017-09-13.Retrieved2017-10-10.
  141. ^"The Nobel Prize in Physiology or Medicine 1934".NobelPrize.org.Retrieved2023-02-23.
  142. ^"Mary Shorb Lecture in Nutrition".Archived fromthe originalon March 4, 2016.RetrievedMarch 3,2016.
  143. ^Shorb MS (May 10, 2012)."Annual Lecture".Department of Animal & Avian Sciences, University of Maryland. Archived fromthe originalon December 12, 2012.RetrievedAugust 2,2014.
  144. ^Hodgkin DC, Pickworth J, Robertson JH, Trueblood KN, Prosen RJ, White JG (1955). "Structure of Vitamin B12: The Crystal Structure of the Hexacarboxylic Acid derived from B12 and the Molecular Structure of the Vitamin".Nature.176(4477): 325–28.Bibcode:1955Natur.176..325H.doi:10.1038/176325a0.PMID13253565.S2CID4220926.
  145. ^Hodgkin DC, Kamper J, Mackay M, Pickworth J, Trueblood KN, White JG (July 1956). "Structure of vitamin B12".Nature.178(4524): 64–66.Bibcode:1956Natur.178...64H.doi:10.1038/178064a0.PMID13348621.S2CID4210164.
  146. ^abDodson G (December 2002). "Dorothy Mary Crowfoot Hodgkin, 12 May 1910 – 29 July 1994".Biographical Memoirs of Fellows of the Royal Society.48:181–219.doi:10.1098/rsbm.2002.0011.PMID13678070.S2CID61764553.
  147. ^Carpenter KJ."The Nobel Prize and the discovery of vitamins".nobelprize.org.Archivedfrom the original on 2023-08-20.Retrieved2023-11-19.
  148. ^abGaby AR (October 2002). "Intravenous nutrient therapy: the" Myers' cocktail "".Altern Med Rev.7(5): 389–403.PMID12410623.
  149. ^Gavura S (24 May 2013)."A closer look at vitamin injections".Science-Based Medicine.Archivedfrom the original on 11 January 2020.Retrieved10 January2020.
  150. ^Bauer BA (29 March 2018)."Are vitamin B-12 injections helpful for weight loss?".Mayo Clinic.Archivedfrom the original on 27 November 2019.Retrieved11 January2020.
  151. ^Silverstein WK, Lin Y, Dharma C, Croxford R, Earle CC, Cheung MC (July 2019)."Prevalence of Inappropriateness of Parenteral Vitamin B12 Administration in Ontario, Canada".JAMA Internal Medicine.179(10): 1434–1436.doi:10.1001/jamainternmed.2019.1859.ISSN2168-6106.PMC6632124.PMID31305876.

External links[edit]

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