Vitamin B12, also known as cobalamin, is a water-soluble vitamin involved in the metabolism of every cell of the human body: it is a cofactor in DNA synthesis, and in both fatty acid and amino acid metabolism. It is particularly important in the normal functioning of the nervous system via its role in the synthesis of myelin, and in the maturation of developing red blood cells in the bone marrow.
|Other names||vitamin B12, vitamin B-12|
|by mouth, sublingual, IV, IM, intranasal|
|Bioavailability||Readily absorbed in distal half of the ileum|
|Protein binding||Very high to specific transcobalamins plasma proteins.|
Binding of hydroxocobalamin is slightly higher than cyanocobalamin.
|Elimination half-life||Approximately 6 days|
(400 days in the liver)
|Chemical and physical data|
|Molar mass||1355.388 g·mol−1|
|3D model (JSmol)|
Vitamin B12 is one of eight B vitamins; it is the largest and most structurally complex vitamin. It consists of a class of chemically related compounds (vitamers), all of which show physiological activity. It contains the biochemically rare element cobalt (chemical symbol Co) positioned in the center of a corrin ring. The only organisms to produce vitamin B12 are certain bacteria, and archaea. Some of these bacteria are found in the soil around the grasses that ruminants eat; they are taken into the animal, proliferate, form part of their gut flora, and continue to produce vitamin B12.
Most omnivorous people in developed countries obtain enough vitamin B12 from consuming animal products, including meat, milk, eggs, and fish. Grain-based foods are often fortified by having the vitamin added to them. Vitamin B12 supplements are available in single agent or multivitamin tablets. Pharmaceutical preparations may be given by intramuscular injection. Because there are few non-animal sources of the vitamin, vegans are advised to consume a dietary supplement or fortified foods for B12 intake, or risk serious health consequences.
The most common cause of vitamin B12 deficiency in developed countries is impaired absorption due to a loss of gastric intrinsic factor, which must be bound to food-source B12 in order for absorption to occur. Another group affected are those on long term antacid therapy, using proton-pump inhibitors, H2 blockers or other antacids. This condition may be characterised by limb neuropathy or a blood disorder called pernicious anemia, a type of megaloblastic anemia. Folate levels in the individual may affect the course of pathological changes and symptomatology. Deficiency is more likely after age 60, and increases in incidence with advancing age. Dietary deficiency is very rare in developed countries due to access to dietary meat and fortified foods, but children in some regions of developing countries are at particular risk due to increased requirements during growth coupled with lack of access to dietary B12; adults in these regions are also at risk. Other causes of vitamin B12 deficiency are much less frequent.
Vitamin B12 deficiency can potentially cause severe and irreversible damage, especially to the brain and nervous system. At levels only slightly lower than normal, a range of symptoms such as fatigue, lethargy, difficulty walking (staggering balance problems) depression, poor memory, breathlessness, headaches, and pale skin, among others, may be experienced, especially in elderly people (over age 60) who produce less stomach acid as they age, thereby increasing their probability of B12 deficiencies. Vitamin B12 deficiency can also cause symptoms of mania and psychosis.
Vitamin B12 deficiency is most commonly caused by low intakes, but can also result from malabsorption, certain intestinal disorders, low presence of binding proteins, and use of certain medications. Vitamin B12 is rare from plant sources, so vegetarians are more likely to suffer from vitamin B12 deficiency. Infants are at a higher risk of vitamin B12 deficiency if they were born to vegetarian mothers. The elderly who have diets with limited meat or animal products are vulnerable populations as well. Vitamin B12 deficiency may occur in between 40% to 80% of the vegetarian population who are not also consuming a vitamin B12 supplement. In Hong Kong and India, vitamin B12 deficiency has been found in roughly 80% of the vegan population as well. Vegans can avoid this by eating B12-fortified foods like cereals, plant-based milks, and nutritional yeast as a regular part of their diet. In addition to worries concerning those following a vegetarian or vegan diet, research has found that approximately 39 percent of the general population may have possible B12 deficiencies or difficulty with the absorption of this nutrient. Taking a B12 supplement could be beneficial to most people.
B12 is a co-substrate of various cell reactions involved in methylation synthesis of nucleic acid and neurotransmitters. Synthesis of the trimonoamine neurotransmitters can enhance the effects of a traditional antidepressant. The intracellular concentrations of vitamin B12 can be inferred through the total plasma concentration of homocysteine, which can be converted to methionine through an enzymatic reaction that uses 5-methyltetrahydrofolate as the methyl donor group. Consequently, the plasma concentration of homocysteine falls as the intracellular concentration of vitamin B12 rises. The active metabolite of vitamin B12 is required for the methylation of homocysteine in the production of methionine, which is involved in a number of biochemical processes including the monoamine neurotransmitters metabolism. Thus, a deficiency in vitamin B12 may impact the production and function of those neurotransmitters.
Repletion of deficiency
Severe vitamin B12 deficiency is corrected with frequent intramuscular injections of large doses of the vitamin, followed by maintenance doses at longer intervals. Tablets are sometimes used for repletion in mild deficiency; and for maintenance regardless of severity. Vitamin B12 supplementation sometimes leads to acneiform eruptions (acne-like rashes).
For cyanide poisoning, a large amount of hydroxocobalamin may be given intravenously and sometimes in combination with sodium thiosulfate. The mechanism of action is straightforward: the hydroxycobalamin hydroxide ligand is displaced by the toxic cyanide ion, and the resulting harmless B12 complex is excreted in urine. In the United States, the Food and Drug Administration approved the use of hydroxocobalamin for acute treatment of cyanide poisoning.
The U.S. Institute of Medicine (renamed National Academy of Medicine in 2015) updated estimated average requirement (EAR) and recommended dietary allowance (RDA) for vitamin B12 in 1998. The EAR for vitamin B12 for women and men ages 14 and up is 2.0 μg/day; the RDA is 2.4 μg/day. RDA is higher than EAR so as to identify amounts that will cover people with higher than average requirements. RDA for pregnancy equals 2.6 μg/day. RDA for lactation equals 2.8 μg/day. For infants up to 12 months the adequate intake (AI) is 0.4–0.5 μg/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 1.8 μg/day. Because 10 to 30 percent of older people may be unable to effectively absorb vitamin B12 naturally occurring in foods, it is advisable for those older than 50 years to meet their RDA mainly by consuming foods fortified with vitamin B12 or 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 B12 there 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 as dietary reference intakes (DRIs).
The European 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 defined the same as in the United States. For women and men over age 18 the adequate intake (AI) is set at 4.0 μg/day. AI for pregnancy is 4.5 μg/day, for lactation 5.0 μg/day. For children aged 1–17 years the AIs increase with age from 1.5 to 3.5 μg/day. These AIs are higher than the U.S. RDAs. 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.
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 B12 labeling purposes 100% of the daily value was 6.0 μg, but on 27 May 2016, it was revised downward to 2.4 μg. A table of the old and new adult daily values is provided in the "Reference Daily Intake" article. The original deadline to be in compliance was 28 July 2018, but on 29 September 2017, the Food and Drug Administration (FDA) released a proposed rule that extended the deadline to 1 January 2020 for large companies, and 1 January 2021 for small companies.
Bacteria and archaea
Vitamin B12 is produced in nature by certain bacteria, and archaea. It is synthesized by some bacteria in the gut flora in humans and other animals, but humans cannot absorb this as it is made in the colon, downstream from the small intestine, where the absorption of most nutrients occurs. Ruminants, such as cows and sheep, are foregut fermenters, and absorb vitamin B12 produced by bacteria in their guts. Other mammalian species (examples: rabbits, pikas, beaver, guinea pigs) consume high-fiber plants which pass through the intestinal system and undergo bacterial fermentation in the cecum and large intestine. The first-passage feces produced by this hindgut fermentation, called "cecotropes", are reingested, a practice referred to as cecotrophy or coprophagy. Reingestion allows for absorption of nutrients made available by bacterial digestion, and also of vitamins and other nutrients synthesized by the gut bacteria, including vitamin B12. Second-passage feces have a different composition and are not reingested. For gut bacteria to produce vitamin B12 the animal must consume sufficient amounts of cobalt.
Animals store vitamin B12 in the liver and muscles and some pass the vitamin into their eggs and milk; meat, liver, eggs and milk are therefore sources of the vitamin for other animals as well as humans. For humans, the bioavailability from eggs is less than 9%, compared to 40% to 60% from fish, fowl and meat. Insects are a source of B12 for animals (including other insects and humans).
Plants and algae
Natural plant and algae sources of vitamin B12 include fermented plant foods such as tempeh and seaweed-derived foods such as nori and laver. Other types of algae are rich in B12, with some species, such as Porphyra yezoensis, containing as much cobalamin as liver. Methylcobalamin has been identified in Chlorella vulgaris. 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, or in the case of fermented plant foods, from bacterial fermentation.
The UK Vegan Society, the Vegetarian Resource Group, and the Physicians Committee for Responsible Medicine, among others, recommend that every vegan who is not consuming adequate B12 from fortified foods take supplements. Foods for which vitamin B12-fortified versions are widely available include breakfast cereals, soy products, energy bars, and nutritional yeast.
Vitamin B12 is included in multivitamin pills; and 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 5,000 µg each, and it is a common ingredient in energy drinks and energy shots, usually at many times the recommended dietary allowance of B12. The vitamin can also be a prescription product via injection or other means.
Sublingual methylcobalamin, which contains no cyanide, is available in 5-mg tablets. The metabolic fate and biological distribution of methylcobalamin are expected to be similar to that of other sources of vitamin B12 in the diet. The amount of cyanide in cyanocobalamin is not a concern though, even in the 1,000-µg dose – since the amount of cyanide there (20 µg in a 1,000-µg cyanocobalamin tablet) is less than the daily consumption of cyanide from food, and so cyanocobalamin is not considered a health risk.
Injected and transdermal administration
Injection and patches are sometimes used if digestive absorption is impaired, but this course of action may not be necessary with high-potency oral supplements (such as 0.5–1 mg or more) because with large quantities of the vitamin taken orally, even the 1% to 5% of the free crystalline B12 that is absorbed along the entire intestine by passive diffusion may be sufficient to provide necessary amount.
A person with cobalamin C disease (which results in combined methylmalonic aciduria and homocystinuria) may require treatment with intravenous or intramuscular hydroxocobalamin or transdermal B12, because cyanocobalamin is inadequate in the treatment of cobalamin C disease.
Pseudovitamin-B12 refers to B12-like analogues that are biologically inactive in humans and yet found to be present alongside B12 in humans, many food sources (including animals), and possibly supplements and fortified foods. Most cyanobacteria, including Spirulina, and some algae, such as dried Asakusa-nori (Porphyra tenera), have been found to contain mostly pseudovitamin-B12 instead of biologically active B12.
H2-receptor antagonists and proton-pump inhibitors
Gastric acid is needed to release vitamin B12 from protein for absorption. Reduced secretion of gastric acid and pepsin produced by H2 blocker or proton-pump inhibitor (PPI) drugs can reduce absorption of protein-bound (dietary) vitamin B12, although not of supplemental vitamin B12. H2-receptor antagonist examples include cimetidine, famotidine, nizatidine, and ranitidine. PPIs examples include omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole. Clinically significant vitamin B12 deficiency and megaloblastic anemia are unlikely, unless these drug therapies are prolonged for two or more years, or if in addition the person's diet is below recommended intakes. Symptomatic vitamin deficiency is more likely if the person is rendered achlorhydric (complete absence of gastric acid secretion), which occurs more frequently with proton pump inhibitors than H2 blockers.
Reduced serum levels of vitamin B12 occur in up to 30% of people taking long-term anti-diabetic metformin. Deficiency does not develop if dietary intake of vitamin B12 is adequate or prophylactic B12 supplementation is given. If the deficiency is detected, metformin can be continued while the deficiency is corrected with B12 supplements.
B12 is the most chemically complex of all the vitamins. The structure of B12 is based on a corrin ring, which is similar to the porphyrin ring found in heme. The central metal ion is cobalt. Four of the six coordination sites are provided by the corrin ring, and a fifth by a dimethylbenzimidazole group. The sixth coordination site, the reactive center, is variable, being a cyano group (–CN), a hydroxyl group (–OH), a methyl group (–CH3) or a 5′-deoxyadenosyl group (here the C5′ atom of the deoxyribose forms the covalent bond with cobalt respectively, to yield the four vitamers (forms) of B12. Historically, the covalent C-Co bond is one of the first examples of carbon-metal bonds to be discovered in biology. The hydrogenases and, by necessity, enzymes associated with cobalt utilization, involve metal-carbon bonds.
Vitamin B12 is a generic descriptor name referring to a collection of cobalt and corrin ring molecules, which are defined by their particular vitamin function in the body. All of the substrate cobalt-corrin molecules from which B12 is made must be synthesized by bacteria. After this synthesis is complete, the human body has the ability (except in rare cases) to convert any form of B12 to an active form, by means of enzymatically removing certain prosthetic chemical groups from the cobalt atom and replacing them with others.
The four vitamers of B12 are all deeply red-colored crystals and water solutions, due to the color of the cobalt-corrin complex.
- Cyanocobalamin is one form of B12 because it can be metabolized in the body to an active coenzyme form. The cyanocobalamin form of B12 does not occur in nature normally, but is a byproduct of the fact that other forms of B12 are avid binders of cyanide (–CN) which they pick up in the process of activated charcoal purification of the vitamin after it is made by bacteria in the commercial process. Since the cyanocobalamin form of B12 is easy to crystallize and is not sensitive to air-oxidation, it is typically used as a form of B12 for food additives and in many common multivitamins. 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 vitamer of B12 commonly encountered in pharmacology, but is not normally present in the human body. Hydroxocobalamin is sometimes denoted B12a. This is the form of B12 produced by bacteria, and which is converted to cyanocobalamin in the commercial charcoal filtration step of production. Hydroxocobalamin has an avid affinity for cyanide ions 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 longer retention times in the body, has been used for vitamin replacement in situations where added reassurance of activity is desired. Intramuscular administration of hydroxocobalamin is also the preferred treatment for pediatric patients 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 for treatment of patients with pernicious anemia who have optic neuropathy.
- Adenosylcobalamin (adoB12 or AdoCbl) and methylcobalamin (MeB12 or MeCbl) are the two enzymatically active cofactor forms of B12 that naturally occur in the body. Most of the body's reserves are stored as adoB12 in the liver. These are converted to the other methylcobalamin form as needed.
A review of what is reported in the literature about cobalamin chemistry, transport, and processing suggests that despite the increased cost, there is unlikely to be any advantage to the use of adenosylcobalamin or methylcobalamin for treatment of vitamin B12 deficiency over the other two forms except possibly in very rare circumstances in which an inborn metabolic disorder reduces the efficiency of the conversion of cyanocobalamin to MeCbl or AdoCbl. The use of parenteral hydroxocobalamin has been suggested in these cases. However, due to its excellent shelf-life and stability, cyanocobalamin is still considered the best choice for oral administration. (For the treatment of cyanide poisoning, hydroxocobalamin is the required form.)
Vitamin B12 functions as a coenzyme, meaning that its presence is required for enzyme-catalyzed reactions. Three types of enzymes:
- 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.
- Methyl (–CH3) group transfers between two molecules. These use MeB12 (methylcobalamin) form of the vitamin.
- Reactions in which a halogen atom is removed from an organic molecule. Enzymes in this class have not been identified in humans.
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:
- 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 in the extraction of energy from proteins and fats. This functionality is lost in vitamin B12 deficiency, and can be measured clinically as an increased methylmalonic acid (MMA) level. Unfortunately, an elevated MMA is a sensitive but not specific test, and not all who have it actually have B12 deficiency. For example, MMA is elevated in 90–98% of patients with B12 deficiency; 20–25% of patients over the age of 70 have elevated levels of MMA, yet 25–33% of them do not have B12 deficiency. For this reason, assessment of MMA levels is not routinely recommended in the elderly. There is no "gold standard" test for B12 deficiency because as a B12 deficiency occurs, serum values may be maintained while tissue B12 stores become depleted. Therefore, serum B12 values above the cut-off point of deficiency do not necessarily indicate adequate B12 status. The MUT function is necessary for proper myelin synthesis and is not affected by folate supplementation.
- MTR, also known as methionine synthase, is a methyltransferase enzyme, which uses the MeB12 and reaction type 2 to transfer a methyl group from 5-methyltetrahydrofolate to homocysteine, thereby generating tetrahydrofolate (THF) and methionine. This functionality is lost in vitamin B12 deficiency, resulting in an increased homocysteine level and the trapping of folate as 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 B12 deficiency, including the megaloblastic anemia of pernicious 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 a facultative function which is mediated by B12-conservation of an active form of folate which is needed for efficient DNA production. Other cobalamin-requiring methyltransferase enzymes are also known in bacteria, such as Me-H4-MPT, coenzyme M methyltransferase.
If 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 thus are 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 now more rare. At the same time, since DNA synthetic-sensitive tests for anemia and erythrocyte size are routinely done in even simple medical test clinics (so that these folate-mediated biochemical effects are more often directly detected), the MTR-dependent effects of B12 deficiency are becoming apparent not as anemia due to DNA-synthetic problems (as they were classically), but now mainly as a simple and less obvious elevation of homocysteine in the blood and urine (homocysteinuria). This condition may result in long-term damage to arteries and in clotting (stroke and heart attack), but this effect is difficult to separate from other common processes associated with atherosclerosis and 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 reactions related 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 MMA will prevent normal fatty acid synthesis, or it will be incorporated into fatty acids itself rather than normal malonic acid. If this abnormal fatty acid subsequently is incorporated into myelin, the resulting myelin will be too fragile, and demyelination will occur. Although the precise mechanism or mechanisms are not known with certainty, the result is subacute combined degeneration of spinal cord. Whatever the cause, it is known that B12 deficiency 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 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 with B12 deficiency. Methylation of the myelin sheath phospholipids may also depend on adequate folate, which in turn is dependent on MTR recycling, unless ingested in relatively high amounts.
Methyl-B12 is absorbed by two processes. The first is an intestinal mechanism using intrinsic factor through which 1–2 micrograms can be absorbed every few hours. The second is a diffusion process by which approximately 1% of the remainder is absorbed. The human physiology of vitamin B12 is complex, and therefore is prone to mishaps leading to vitamin B12 deficiency. Protein-bound vitamin B12 must be released from the proteins by the action of digestive proteases in both the stomach and small intestine. Gastric acid releases the vitamin from food particles; therefore antacid and acid-blocking medications (especially proton-pump inhibitors) may inhibit absorption of B12.
B12 taken in a low-solubility, non-chewable supplement pill form may bypass the mouth and stomach and not mix with gastric acids, but acids are not necessary for the absorption of free B12 not bound to protein; acid is necessary only to recover naturally-occurring vitamin B12 from foods.
R-protein (also known as haptocorrin and cobalophilin) is a B12 binding protein that is produced in the salivary glands. It must wait to bind food-B12 until B12 has been freed from proteins in food by pepsin in the stomach. B12 then binds to the R-protein to avoid degradation of it in the acidic environment of the stomach.
This pattern of B12 transfer to a special binding protein secreted in a previous digestive step, is repeated once more before absorption. The next binding protein for B12 is intrinsic factor (IF), a protein synthesized by gastric parietal cells that is secreted in response to histamine, gastrin and pentagastrin, as well as the presence of food. In the duodenum, proteases digest R-proteins and release their bound B12, which then binds to IF, to form a complex (IF/B12). B12 must be attached to IF for it to be efficiently absorbed, as receptors on the enterocytes in the terminal ileum of the small bowel only recognize the B12-IF complex; in addition, intrinsic factor protects the vitamin from catabolism by intestinal bacteria.
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 who lack intrinsic factor have a decreased ability to absorb B12. In pernicious anemia, there is a lack of IF due to autoimmune atrophic gastritis, in which antibodies form against parietal cells. Antibodies may alternately form against and bind to IF, inhibiting it from carrying out its B12 protective function. Due to the complexity of B12 absorption, geriatric patients, many of whom are hypoacidic due to reduced parietal cell function, have an increased risk of B12 deficiency. This results in 80–100% excretion of oral doses in the feces versus 30–60% excretion in feces as seen in individuals with adequate IF.
Once the IF/B12 complex is recognized by specialized ileal receptors, it is transported into the portal circulation. The vitamin is then transferred to transcobalamin II (TC-II/B12), which serves as the plasma transporter. Hereditary defects in production of the transcobalamins and their receptors may produce functional deficiencies in B12 and infantile megaloblastic anemia, and abnormal B12 related biochemistry, even in some cases with normal blood B12 levels. For the vitamin to serve inside cells, the TC-II/B12 complex must bind to a cell receptor, and be endocytosed. The transcobalamin-II is degraded within a lysosome, and free B12 is finally released into the cytoplasm, where it may be transformed into the proper coenzyme, by certain cellular enzymes (see above).
Investigations into the intestinal absorption of B12 point out that the upper limit of absorption per single oral dose, under normal conditions, is about 1.5 µg: "Studies in normal persons indicated that about 1.5 µg is assimilated when a single dose varying from 5 to 50 µg is administered by mouth. In a similar study Swendseid et al. stated that the average maximum absorption was 1.6 µg [...]" The bulk diffusion process of B12 absorption noted in the first paragraph above, may overwhelm the complex R-factor and IGF-factor dependent absorption, when oral doses of B12 are very large (a thousand or more µg per dose) as commonly happens in dedicated-pill oral B12 supplementation. It is this last fact which allows pernicious anemia and certain other defects in B12 absorption to be treated with oral megadoses of B12, even without any correction of the underlying absorption defects. See the section on supplements above.
Storage and excretion
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. 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; most of the B12 secreted in the bile is recycled via enterohepatic circulation. Excess B12 beyond 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. How fast B12 levels change depends on the balance between how much B12 is obtained from the diet, how much is secreted and how much is absorbed. B12 deficiency may arise in a year if initial stores are low and genetic factors unfavourable, or may not appear for decades. In infants, B12 deficiency can appear much more quickly.
Industrial production of B12 is achieved through fermentation of selected microorganisms. Streptomyces griseus, a bacterium once thought to be a fungus, was the commercial source of vitamin B12 for many years. The species Pseudomonas denitrificans and Propionibacterium freudenreichii subsp. shermanii are more commonly used today. These are frequently grown under special conditions to enhance yield, and at least one company uses genetically engineered versions of one or both of these species. Since a number of species of Propionibacterium produce no exotoxins or endotoxins and are generally recognized as safe (have been granted GRAS status) by the Food and Drug Administration of the United States, they are presently the FDA-preferred bacterial fermentation organisms for vitamin B12 production.
No eukaryotic organisms (including plants, animals, and fungi) are independently capable of constructing vitamin B12. Only bacteria and archaea have the enzymes required for its biosynthesis. Like all tetrapyrroles, it is derived from uroporphyrinogen III. This porphyrinogen is methylated at two pyrrole rings to give dihydrosirohydrochlorin, which is oxidized to sirohydrochlorin, which undergoes further reactions, notably a ring contraction, to give the corrin ring.
The complete laboratory synthesis of B12 was achieved by Robert Burns Woodward and Albert Eschenmoser in 1972, and remains one of the classic feats of organic synthesis, requiring the effort of 91 postdoctoral fellows (mostly at Harvard) and 12 PhD students (at ETH 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 B12 was previously reported. Though it constitutes an intellectual achievement of the highest caliber, the Eschenmoser–Woodward synthesis of vitamin B12 is of no practical consequence due to its length, taking 72 chemical steps and giving an overall chemical yield well under 0.01%. And although there have been sporadic synthetic efforts since 1972, the Eschenmoser–Woodward synthesis remains the only completed (formal) total synthesis. Bacterial (or, perhaps archaeal) fermentation remains the only industrially viable source of the vitamin for food production and medicine.
Species from the following genera and the following individual species are known to synthesize B12: Propionibacterium shermanii, Pseudomonas denitrificans, Streptomyces griseus, Acetobacterium, Aerobacter, Agrobacterium, Alcaligenes, Azotobacter, Bacillus, Clostridium, Corynebacterium, Flavobacterium, Lactobacillus, Micromonospora, Mycobacterium, Nocardia, Protaminobacter, Proteus, Rhizobium, Salmonella, Serratia, Streptococcus and Xanthomonas.
- 1849 – Thomas Addison first described a case of pernicious anemia.
- 1877 – William Osler and William Gardner first described a case of neuropathy in this condition.
- 1878 – Hayem first described large red cells in the peripheral blood in this condition, which he called "giant blood corpuscles", now called macrocytes.
- 1880 – Paul Ehrlich first identified megaloblasts in the bone marrow in this condition.
- 1887 – Ludwig Lichtheim first described a case of myelopathy in this condition.
- 1920 – George Whipple discovered that ingesting large amounts of liver seemed to most rapidly cure the anemia of blood loss in dogs, and hypothesized that eating liver might treat pernicious anemia.
- 1926 – George Minot shared the 1934 Nobel Prize with William Murphy and George Whipple, for discovery of an effective treatment for pernicious anemia using liver concentrate, later found to contain a large amount of vitamin B12.
- 1928 – Edwin Cohn prepared a liver extract that was 50 to 100 times more potent in treating pernicious anema than the natural liver products. Whipple, Minot, and Murphy shared the 1934 Nobel Prize in Physiology or Medicine.
- 1929 – William Castle demonstrated that gastric juice contained an "intrinsic factor" which when combined with meat ingestion resulted in absorption of the vitamin in this condition.
- 1947 – Mary Shaw Shorb, in a collaborative project with Karl Folkers, was provided with a US$400 grant to develop the so-called "LLD assay" for B12. LLD stood for Lactobacillus lactis Dorner, a strain of bacterium which required "LLD factor" for growth, which was eventually identified as B12.
- 1948 – Shorb and colleagues Karl A. Folkers and Alexander R. Todd used the LLD assay to rapidly extract the anti-pernicious anemia factor from liver extracts, and pure B12 was isolated.
- 1949 – Shorb and Folkers received the Mead Johnson Award from the American Society of Nutritional Sciences for their discovery.
- 1956 – The chemical structure of the molecule was determined by Dorothy Hodgkin, based on crystallographic data. She was awarded the 1964 Nobel Prize in Chemistry for determining the structure of vitamin B12 and other complex molecules.
- 1959 – methods of producing the vitamin in large quantities from bacteria cultures were developed.
- 1981 – Observations of stereospecificity encountered by R. B. Woodward during the synthesis of vitamin B12 led to the formulation of the principle of the conservation of orbital symmetry, which would result in a Nobel Prize in Chemistry shared by R. Hoffmann and K. Fukui.
- "Vitamin B12: Fact Sheet for Health Professionals". Office of Dietary Supplements, US National Institutes of Health. 9 July 2019. Retrieved 1 November 2019.
- "Vitamin B12". Micronutrient Information Center, Linus Pauling Institute, Oregon State University, Corvallis, OR. 4 June 2015. Retrieved 5 April 2019.
- Yamada K (2013). "Chapter 9. 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. 13. Springer. pp. 295–320. doi:10.1007/978-94-007-7500-8_9. ISBN 978-94-007-7499-5. PMID 24470095.
- Miller A, Korem M, Almog R, Galboiz Y (June 2005). "Vitamin B12, demyelination, remyelination and repair in multiple sclerosis". Journal of the Neurological Sciences. 233 (1–2): 93–7. doi:10.1016/j.jns.2005.03.009. PMID 15896807.
- Greer JP (2014). Wintrobe's Clinical Hematology Thirteenth Edition. Philadelphia, PA: Wolters Kluwer/Lippincott Williams & Wilkins. ISBN 978-1-4511-7268-3. Chapter 36: Megaloblastic anemias: disorders of impaired DNA synthesis by Ralph Carmel
- "Foods highest in Vitamin B12 (based on levels per 100-gram serving)". Nutrition Data. Condé Nast, USDA National Nutrient Database, release SR-21. 2014. Retrieved February 16, 2017.
- "What Every Vegan Should Know About Vitamin B12". The Vegan Society. 2012-06-12. Retrieved 2018-10-15.
- "Acid-Reflux Drugs Tied to Lower Levels of Vitamin B-12".
- 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): 243–70. doi:10.1177/153537020122600402. PMID 11368417.
- Skerrett, Patrick J. (2013-01-10). "Vitamin B12 deficiency can be sneaky, harmful". Harvard Health Blog. Retrieved 2018-12-14.
- "Vitamin B12 or folate deficiency anaemia – Symptoms". National Health Service, England. May 16, 2016. Retrieved February 16, 2017.
- 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): 701–3. PMID 11574992.
- 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): 110–7. doi:10.1111/nure.12001. PMID 23356638.
- Woo KS, Kwok TC, Celermajer DS (August 2014). "Vegan diet, subnormal vitamin B-12 status and cardiovascular health". Nutrients. 6 (8): 3259–73. doi:10.3390/nu6083259. PMC 4145307. PMID 25195560.
- Tucker KL, Rich S, Rosenberg I, Jacques P, Dallal G, Wilson PW, Selhub J (February 2000). "Plasma vitamin B-12 concentrations relate to intake source in the Framingham Offspring study". The American Journal of Clinical Nutrition. 71 (2): 514–22. doi:10.1093/ajcn/71.2.514. PMID 10648266.
- Biemans E, Hart HE, Rutten GE, Cuellar Renteria VG, Kooijman-Buiting AM, Beulens JW (April 2015). "Cobalamin status and its relation with depression, cognition and neuropathy in patients with type 2 diabetes mellitus using metformin". Acta Diabetologica. 52 (2): 383–93. doi:10.1007/s00592-014-0661-4. PMID 25315630.
- Bottiglieri T, Laundy M, Crellin R, Toone BK, Carney MW, Reynolds EH (August 2000). "Homocysteine, folate, methylation, and monoamine metabolism in depression". Journal of Neurology, Neurosurgery, and Psychiatry. 69 (2): 228–32. doi:10.1136/jnnp.69.2.228. PMC 1737050. PMID 10896698.
- Kang D, Shi B, Erfe MC, Craft N, Li H (June 2015). "Vitamin B12 modulates the transcriptome of the skin microbiota in acne pathogenesis". Science Translational Medicine. 7 (293): 293ra103. doi:10.1126/scitranslmed.aab2009. PMC 6049814. PMID 26109103.
- 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. PMID 3295013.
- 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 (Suppl. 1): 1–3. doi:10.1080/15563650600811607. PMID 16990188.
- Institute 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. ISBN 978-0-309-06554-2. Retrieved February 7, 2012.
- "Overview on Dietary Reference Values for the EU population as derived by the EFSA Panel on Dietetic Products, Nutrition and Allergies" (PDF). 2017.
- "Tolerable Upper Intake Levels For Vitamins And Minerals" (PDF). European Food Safety Authority. 2006.
- "Food Labeling: Revision of the Nutrition and Supplement Facts Labels" (PDF). Federal Register. May 27, 2016. p. 33982.
- "Changes to the Nutrition Facts Label". Food and Drug Administration (FDA). June 18, 2019. Retrieved July 16, 2019.
This article incorporates text from this source, which is in the public domain.
- Watanabe F, Yabuta Y, Bito T, Teng F (May 2014). "Vitamin B₁₂-containing plant food sources for vegetarians". Nutrients. 6 (5): 1861–73. doi:10.3390/nu6051861. PMC 4042564. PMID 24803097.
- Fang H, Kang J, Zhang D (January 2017). "12: a review and future perspectives". Microbial Cell Factories. 16 (1): 15. doi:10.1186/s12934-017-0631-y. PMC 5282855. PMID 28137297.
- Moore SJ, Warren MJ (June 2012). "The anaerobic biosynthesis of vitamin B12". Biochemical Society Transactions. 40 (3): 581–6. doi:10.1042/BST20120066. PMID 22616870.
- Graham RM, Deery E, Warren MJ (2009). "18: Vitamin B12: Biosynthesis of the Corrin Ring". In Warren MJ, Smith AG (eds.). Tetrapyrroles Birth, Life and Death. New York, NY: Springer-Verlag. p. 286. doi:10.1007/978-0-387-78518-9_18. ISBN 978-0-387-78518-9.
- Gille D, Schmid A (February 2015). "Vitamin B12 in meat and dairy products". Nutrition Reviews. 73 (2): 106–15. doi:10.1093/nutrit/nuu011. PMID 26024497.
- Stevens 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.19184.108.40.2063. PMID 9562034.
- McDowell LR (2008). Vitamins in Animal and Human Nutrition (2nd ed.). Hoboken: John Wiley & Sons. pp. 525, 539. ISBN 9780470376683.
- Rooke J (October 30, 2013). "Do carnivores need Vitamin B12 supplements?". Baltimore Post Examiner.
- Watanabe F (November 2007). "Vitamin B12 sources and bioavailability". Experimental Biology and Medicine. 232 (10): 1266–74. doi:10.3181/0703-MR-67. PMID 17959839.
- Dossey AT (February 1, 2013). "Why Insects Should Be in Your Diet". The Scientist.
- "Vitamin B12 content, all foods ordered by content in µg per 100 g". United States Department of Agriculture, Agricultural Research Service, National Nutrient Database for Standard Reference, Release 28. May 2016. Retrieved April 6, 2017.
- Liem IT, Steinkraus KH, Cronk TC (December 1977). "Production of vitamin B-12 in tempeh, a fermented soybean food". Applied and Environmental Microbiology. 34 (6): 773–6. PMC 242746. PMID 563702.
- Keuth, S; Bisping, B (May 1994). "Vitamin B12 production by Citrobacter freundii and Klebsiella pneumoniae during tempeh fermentation" (PDF). Applied and Environmental Microbiology. 60 (5): 1495–9. PMC 201508. PMID 8017933.
- 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): 2418–25. doi:10.1016/j.foodchem.2013.05.017. PMID 23870976.
- 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. PMC 2895704. PMID 20607069.
- 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. PMC 3062981. PMID 21436999.
- Croft MT, Lawrence AD, Raux-Deery E, Warren MJ, Smith AG (November 2005). "Algae acquire vitamin B12 through a symbiotic relationship with bacteria". Nature. 438 (7064): 90–3. Bibcode:2005Natur.438...90C. doi:10.1038/nature04056. PMID 16267554.
- 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: 316–20. doi:10.1016/j.foodchem.2014.08.035. PMID 25306351.
- Smith, AG; et al. (2019-09-21). "Plants need their vitamins too". Current Opinion in Plant Biology. 10 (3): 266–75. doi:10.1016/j.pbi.2007.04.009. PMID 17434786.
- Walsh S. "Vegan Society B12 factsheet". Vegan Society. Archived from the original on May 26, 2008. Retrieved January 17, 2008.
- Mangels R. "Vitamin B12 in the Vegan Diet". Vegetarian Resource Group. Retrieved January 17, 2008.
- "Don't Vegetarians Have Trouble Getting Enough Vitamin B12?". Physicians Committee for Responsible Medicine. Retrieved January 17, 2008.
- European Food Safety Authority (September 25, 2008). "5′-deoxyadenosylcobalamin and methylcobalamin as sources for Vitamin B12 added 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 B12 in the diet."
- Bolaman Z, Kadikoylu G, Yukselen V, Yavasoglu I, Barutca S, Senturk T (December 2003). "Oral versus intramuscular cobalamin treatment in megaloblastic anemia: a single-center, prospective, randomized, open-label study". Clinical Therapeutics. 25 (12): 3124–34. doi:10.1016/S0149-2918(03)90096-8. PMID 14749150.
- Lane LA, Rojas-Fernandez C (2002). "Treatment of vitamin b(12)-deficiency anemia: oral versus parenteral therapy". The Annals of Pharmacotherapy. 36 (7–8): 1268–72. doi:10.1345/aph.1A122. PMID 12086562.
- Butler CC, Vidal-Alaball J, Cannings-John R, McCaddon A, Hood K, Papaioannou A, Mcdowell I, Goringe A (June 2006). "Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency: a systematic review of randomized controlled trials". Family Practice. 23 (3): 279–85. doi:10.1093/fampra/cml008. PMID 16585128.
- Shipton MJ, Thachil J (April 2015). "Vitamin B12 deficiency – A 21st century perspective". Clinical Medicine. 15 (2): 145–50. doi:10.7861/clinmedicine.15-2-145. PMC 4953733. PMID 25824066.
- Silverstein WK, Lin Y, Dharma C, Croxford R, Earle CC, Cheung MC (July 15, 2019). "Prevalence of Inappropriateness of Parenteral Vitamin B12 Administration in Ontario, Canada". JAMA Internal Medicine. 179 (10): 1434. doi:10.1001/jamainternmed.2019.1859. ISSN 2168-6106. PMC 6632124. PMID 31305876.
- Akkuş Arslan, Ş; Arslan, İ; Tirnaksiz, F (2013). "Cobalamins and Methylcobalamin: Coenzyme of Vitamin B12" (PDF). FABAD J. Pharm. Sci. 38 (3): 151–7.
- Andersson HC, Shapira E (January 1998). "Biochemical and clinical response to hydroxocobalamin versus cyanocobalamin treatment in patients with methylmalonic acidemia and homocystinuria (cblC)". The Journal of Pediatrics. 132 (1): 121–4. doi:10.1016/S0022-3476(98)70496-2. PMID 9470012.
- Roze E, Gervais D, Demeret S, Ogier de Baulny H, Zittoun J, Benoist JF, Said G, Pierrot-Deseilligny C, Bolgert F (October 2003). "Neuropsychiatric disturbances in presumed late-onset cobalamin C disease". Archives of Neurology. 60 (10): 1457–62. doi:10.1001/archneur.60.10.1457. PMID 14568819.
- Thauvin-Robinet C, Roze E, Couvreur G, Horellou MH, Sedel F, Grabli D, Bruneteau G, Tonneti C, Masurel-Paulet A, Perennou D, Moreau T, Giroud M, de Baulny HO, Giraudier S, Faivre L (June 2008). "The adolescent and adult form of cobalamin C disease: clinical and molecular spectrum". Journal of Neurology, Neurosurgery, and Psychiatry. 79 (6): 725–8. doi:10.1136/jnnp.2007.133025. PMID 18245139.
- Heil SG, Hogeveen M, Kluijtmans LA, van Dijken PJ, van de Berg GB, Blom HJ, Morava E (October 2007). "Marfanoid features in a child with combined methylmalonic aciduria and homocystinuria (CblC type)". Journal of Inherited Metabolic Disease. 30 (5): 811. doi:10.1007/s10545-007-0546-6. PMID 17768669.
- Tsai AC, Morel CF, Scharer G, Yang M, Lerner-Ellis JP, Rosenblatt DS, Thomas JA (October 2007). "Late-onset combined homocystinuria and methylmalonic aciduria (cblC) and neuropsychiatric disturbance". American Journal of Medical Genetics. Part A. 143A (20): 2430–4. doi:10.1002/ajmg.a.31932. PMID 17853453.
- Oussalah A, Levy J, Filhine-Trésarrieu P, Namour F, Guéant JL (October 2017). "TCN2 rs1801198 c.776G>C polymorphism with markers of one-carbon metabolism and related diseases: a systematic review and meta-analysis of genetic association studies". The American Journal of Clinical Nutrition. 106 (4): 1142–1156. doi:10.3945/ajcn.117.156349. PMC 5611783. PMID 28814397.
- Albert MJ, Mathan VI, Baker SJ (February 1980). "Vitamin B12 synthesis by human small intestinal bacteria". Nature. 283 (5749): 781–2. Bibcode:1980Natur.283..781A. doi:10.1038/283781a0. PMID 7354869.
- Kelly RJ, Gruner TM, Furlong JM, Sykes AR (August 2006). "Analysis of corrinoids in ovine tissues". Biomedical Chromatography. 20 (8): 806–14. doi:10.1002/bmc.604. PMID 16345011.
- Schmidt A, Call LM, Macheiner L, Mayer HK (May 2019). "Determination of vitamin B12 in 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. PMID 30658738.
- Yamada K, Shimodaira M, Chida S, Yamada N, Matsushima N, Fukuda M, Yamada S (2008). "Degradation of vitamin B12 in dietary supplements". International Journal for Vitamin and Nutrition Research. Internationale Zeitschrift Fur Vitamin- und Ernahrungsforschung. Journal International de Vitaminologie et de Nutrition. 78 (4–5): 195–203. doi:10.1024/0300-98220.127.116.11. PMID 19326342.
- Watanabe F, Katsura H, Takenaka S, Fujita T, Abe K, Tamura Y, Nakatsuka T, Nakano Y (November 1999). "Pseudovitamin B12 is the predominant cobamide of an algal health food, spirulina tablets". Journal of Agricultural and Food Chemistry. 47 (11): 4736–41. doi:10.1021/jf990541b. PMID 10552882.
- 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. Internationale Zeitschrift Fur Vitamin- und Ernahrungsforschung. Journal International de Vitaminologie et de Nutrition. 69 (6): 412–8. doi:10.1024/0300-9818.104.22.1682. PMID 10642899.
- 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. PMID 19713987.
- 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. PMID 27806244.
- Andrès E, Noel E, Goichot B (October 2002). "Metformin-associated vitamin B12 deficiency". Archives of Internal Medicine. 162 (19): 2251–2252. doi:10.1001/archinte.162.19.2251-a. PMID 12390080.
- Gilligan MA (February 2002). "Metformin and vitamin B12 deficiency". Archives of Internal Medicine. 162 (4): 484–485. doi:10.1001/archinte.162.4.484. PMID 11863489.
- Copp S (December 1, 2007). "What effect does metformin have on vitamin B12 levels?". UK Medicines Information, NHS. Archived from the original on September 27, 2007.
- Jaouen G, ed. (2006). Bioorganometallics: Biomolecules, Labeling, Medicine. Weinheim: Wiley-VCH. ISBN 978-3-527-30990-0.
- 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): 1364–72. doi:10.1002/mnfr.201500019. PMC 4692085. PMID 25820384.
- Voet JG, Voet D (1995). Biochemistry. New York: J. Wiley & Sons. p. 675. ISBN 978-0-471-58651-7. OCLC 31819701.
- Banerjee R, Ragsdale SW (2003). "The many faces of vitamin B12: catalysis by cobalamin-dependent enzymes". Annual Review of Biochemistry. 72: 209–47. doi:10.1146/annurev.biochem.72.121801.161828. PMID 14527323.
- Banerjee RV, Matthews RG (March 1990). "Cobalamin-dependent methionine synthase". FASEB Journal. 4 (5): 1450–9. doi:10.1096/fasebj.4.5.2407589. PMID 2407589.
- Wickramasinghe SN (September 1995). "Morphology, biology and biochemistry of cobalamin- and folate-deficient bone marrow cells". Baillière's Clinical Haematology. 8 (3): 441–59. doi:10.1016/S0950-3536(05)80215-X. PMID 8534956.
- Naidich MJ, Ho SU (October 2005). "Case 87: Subacute combined degeneration". Radiology. 237 (1): 101–5. doi:10.1148/radiol.2371031757. PMID 16183926.
- "CerefolinNAC® Caplets" (PDF). intetlab.com.
- Marks AD (2009). Basic Medical Biochemistry: A Clinical Approach (3rd ed.). Lippincott, Williams & Wilkins. p. 757. ISBN 978-0781770224.
- Allen RH, Seetharam B, Podell E, Alpers DH (January 1978). "Effect of proteolytic enzymes on the binding of cobalamin to R protein and intrinsic factor. In vitro evidence that a failure to partially degrade R protein is responsible for cobalamin malabsorption in pancreatic insufficiency". The Journal of Clinical Investigation. 61 (1): 47–54. doi:10.1172/JCI108924. PMC 372512. PMID 22556.
- Combs GF (2008). The vitamins: fundamental aspects in nutrition and health (3rd ed.). Amsterdam: Elsevier Academic Press. ISBN 978-0-12-183492-0. OCLC 150255807.
- Abels J, Vegter JJ, Woldring MG, Jans JH, Nieweg HO (October 1959). "The physiologic mechanism of vitamin B12 absorption". Acta Medica Scandinavica. 165 (2): 105–13. doi:10.1111/j.0954-6820.1959.tb14477.x. PMID 13791463.
- Kuzminski AM, Del Giacco EJ, Allen RH, Stabler SP, Lindenbaum J (August 1998). "Effective treatment of cobalamin deficiency with oral cobalamin". Blood. 92 (4): 1191–8. doi:10.1182/blood.V92.4.1191. PMID 9694707.
- "If a person stops consuming the vitamin, the body's stores of this vitamin usually take about 3 to 5 years to exhaust".
- "B12: An essential part of a healthy plant-based diet". International Vegetarian Union.
- 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. PMID 11935176.
- Linnell JC, Matthews DM (February 1984). "Cobalamin metabolism and its clinical aspects". Clinical Science. 66 (2): 113–121. doi:10.1042/cs0660113. PMID 6420106.
- 21 C.F.R. 184.1945
- De Baets S, Vandedrinck S, Vandamme EJ (2000). "Vitamins and Related Biofactors, Microbial Production". In Lederberg J (ed.). Encyclopedia of Microbiology. 4 (2nd ed.). New York: Academic Press. pp. 837–853. ISBN 978-0-12-226800-7.
- Riaz M, Iqbal F, Akram M (2007). "Microbial production of vitamin B12 by methanol utilizing strain of Pseudomonas species". Pakistan Journal of Biochemistry & Molecular Biology. 1. 40: 5–10.
- Zhang Y (January 26, 2009). "New round of price slashing in vitamin B12 sector (Fine and Specialty)". China Chemical Reporter. Archived from the original on May 13, 2013.
- Loeffler G (2005). Basiswissen Biochemie. Heidelberg: Springer. p. 606. ISBN 978-3-540-23885-0.
- Bertrand EM, Saito MA, Jeon YJ, Neilan BA (May 2011). "Vitamin B₁₂ biosynthesis gene diversity in the Ross Sea: the identification of a new group of putative polar B₁₂ biosynthesizers". Environmental Microbiology. 13 (5): 1285–98. doi:10.1111/j.1462-2920.2011.02428.x. PMID 21410623.
- Khan AG, Eswaran SV (2003). "Woodward's synthesis of vitamin B12". Resonance. 8 (6): 8–16. doi:10.1007/BF02837864.
- Eschenmoser A, Wintner CE (June 1977). "Natural product synthesis and vitamin B12". Science. 196 (4297): 1410–20. Bibcode:1977Sci...196.1410E. doi:10.1126/science.867037. PMID 867037.
- Riether 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.
- "Synthesis of Cyanocobalamin by Robert B. Woodward (1973)". www.synarchive.com. Retrieved 2018-02-15.
- Riether 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.
- "Vegan Sources". VeganHealth.org. Archived from the original on 21 October 2017. Retrieved 21 Dec 2017.
- Perlman D (1959). "Microbial synthesis of cobamides". Advances in Applied Microbiology. 1: 87–122. doi:10.1016/S0065-2164(08)70476-3. ISBN 9780120026012. PMID 13854292.
- Martens JH, Barg H, Warren MJ, Jahn D (March 2002). "Microbial production of vitamin B12". Applied Microbiology and Biotechnology. 58 (3): 275–85. doi:10.1007/s00253-001-0902-7. PMID 11935176.
- The Nobel Prize in Physiology or Medicine 1934, Nobelprize.org, Nobel Media AB 2014. Retrieved December 2, 2015.
- "Mary Shorb Lecture in Nutrition". Retrieved March 3, 2016.
- Shorb MS (May 10, 2012). "Annual Lecture". Department of Animal & Avian Sciences, University of Maryland. Archived from the original on December 12, 2012. Retrieved August 2, 2014.
- Hodgkin DC, Kamper J, Mackay M, Pickworth J, Trueblood KN, White JG, et al. (1956). "Structure of vitamin B12". Nature. 178 (4524): 64–66. Bibcode:1956Natur.178...64H. doi:10.1038/178064a0. PMID 13348621.
- "The Nobel Prize and the Discovery of Vitamins". www.nobelprize.org. Retrieved 2018-02-15.