|Systematic (IUPAC) name|
|Mol. mass||1355.37 g/mol|
|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.
|Half life|| Approximately 6 days|
(400 days in the liver)
Vitamin B12 is a water soluble vitamin with a key role in the normal functioning of the brain and nervous system, and for the formation of blood. It is one of the eight B vitamins. It is normally involved in the metabolism of every cell of the body, especially affecting DNA synthesis and regulation, but also fatty acid synthesis and energy production.
Vitamin B12 is the name for a class of chemically-related compounds, all of which have vitamin activity. It is structurally the most complicated vitamin and it contains the biochemically rare element cobalt. Biosynthesis of the basic structure of the vitamin can only be accomplished by bacteria, but conversion between different forms of the vitamin can be accomplished in the human body. A common synthetic form of the vitamin, cyanocobalamin, does not occur in nature, but is used in many pharmaceuticals, supplements and as food additive, due to its stability and lower cost. In the body it is converted to the physiological forms, methylcobalamin and adenosylcobalamin, leaving behind the cyanide, albeit in minimal concentration. More recently, hydroxocobalamin, methylcobalamin and, adenosylcobalamin can also be found in more expensive pharmacological products and food supplements. The utility of these is presently debated.
Historically, vitamin B12 was discovered from its relationship to the disease pernicious anemia, which is an autoimmune disease that destroys parietal cells in the stomach that secrete intrinsic factor. Intrinsic factor is crucial for the normal absorption of B12, therefore, a lack of intrinsic factor, as seen in pernicious anemia, causes a vitamin B12 deficiency. Many other subtler kinds of vitamin B12 deficiency, and their biochemical effects, have since been elucidated.
The name vitamin B12, known as vitamin B12 (commonly B12 or B12 for short) or also cyanocobalamin generally refers to all forms of the vitamin. Some medical practitioners have suggested that its use be split into two different categories, however.
Finally, so-called Pseudo-B12 refers to B12-like substances which are found in certain organisms, including Spirulina (a cyanobacterium) and some algae. These substances are active in tests of B12 activity by highly sensitive antibody-binding serum assay tests, which measure levels of B12 and B12-like compounds in blood. However, these substances do not have B12 biological activity for humans, a fact which may pose a danger to vegans and others on limited diets who do not ingest B12 producing bacteria, but who nevertheless may show normal "B12" levels in the standard immunoassay which has become the normal medical method for testing for B12 deficiency.
Vitamin B12 is 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. However, after this synthesis is complete, the body has a limited power to convert any form of B12 to another, by means of enzymatically removing certain prosthetic chemical groups from the cobalt atom.
Cyanocobalamin is one such compound that is a vitamin in this B complex, because it can be metabolized in the body to an active co-enzyme form. However, 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 deeply red colored, 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. However, this form is not perfectly synonymous with B12, inasmuch as a number of substances (vitamers) have B12 vitamin activity and can properly be labeled vitamin B12, and cyanocobalamin is but one of them. (Thus, all cyanocobalamin is vitamin B12, but not all vitamin B12 is cyanocobalamin).
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, chlorophyll, and cytochrome. 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 center of reactivity, is variable, being a cyano group (-CN), a hydroxyl group (-OH), a methyl group (-CH3) or a 5'-deoxyadenosyl group (here the C5' atom of the deoxyribose forms the covalent bond with Co), respectively, to yield the four B12 forms mentioned above. Historically, the covalent C-Co bond is one of 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 cannot be made by plants or animals as only bacteria have the enzymes required for its synthesis. The total synthesis of B12 was reported by Robert Burns Woodward and Albert Eschenmoser, and remains one of the classic feats of organic synthesis.
Species from the following genera are known to synthesize B12: Aerobacter, Agrobacterium, Alcaligenes, Azotobacter, Bacillus, Clostridium, Corynebacterium, Flavobacterium, Micromonospora, Mycobacterium, Nocardia, Propionibacterium, Protaminobacter, Proteus, Pseudomonas, Rhizobium, Salmonella, Serratia, Streptomyces, Streptococcus and Xanthomonas. Industrial production of B12 is through fermentation of selected microorganisms. Streptomyces griseus, a bacterium once thought to be a yeast, was the commercial source of vitamin B12 for many years. The species Pseudomonas denitrificans and Propionibacterium shermanii are more commonly used today. These are frequently grown under special conditions to enhance yield, and at least one company, Rhône-Poulenc of France, at one point used genetically engineered versions of one or both of these species. It is not clear whether Sanofi-Aventis, the company which the pharmaceutical division of Rhône-Poulenc merged into, has continued the use of genetically modified organisms.
Vitamin B12 is normally involved in the metabolism of every cell of the body, especially affecting the DNA synthesis and regulation but also fatty acid synthesis and energy production. However, many (though not all) of the effects of functions of B12 can be replaced by sufficient quantities of folic acid (another B vitamin), since B12 is used to regenerate folate in the body. Most "B12 deficient symptoms" are actually folate deficient symptoms, since they include all the effects of pernicious anemia and megaloblastosis, which are due to poor synthesis of DNA when the body does not have a proper supply of folic acid for the production of thymine. When sufficient folic acid is available, all known B12 related deficiency syndromes normalize, save those narrowly connected with the B12 dependent enzymes Methylmalonyl Coenzyme A mutase (MUT), and 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), also known as methionine synthase; and the buildup of their respective substrates (methylmalonic acid, MMA) and homocysteine.
Coenzyme B12's reactive C-Co bond participates in two types of enzyme-catalyzed reactions.
In humans, only two corresponding coenzyme B12-dependent enzymes are known:
If folate is present in quantity, then of the two absolutely B12 dependent reactions, the MUT reaction shows the most direct and characteristic secondary effects, focusing on the nervous system (see below). Since the late 1990s folic acid has begun to be added to fortify flour in many countries, so that 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-sythetic problems (as they were classically), but now mainly as a simple and less obvious elevation of homocysteine in the blood and urine, called (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 B12-dependent MTR reactions may 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.
The specific myelin damage resulting from B12 deficiency, even in the presense of adequete folate and methionine, 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 methylmalonic acid (MMA), a myelin destabilizer. Excessive MMA will prevent normal fatty acid synthesis, or it will be incorporated into fatty acid 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(s) are not known with certainty, the result is subacute combined degeneration of central nervous system and 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.
The human physiology of vitamin B12 is complex, and therefore is prone to mishaps leading to vitamin B12 deficiency. Unlike most nutrients, absorption of vitamin B12 actually begins in the mouth where small amounts of unbound crystalline B12 can be absorbed through the mucosa membrane. Food protein bound vitamin B12 is digested in the stomach by proteolytic gastric enzymes, which require an acid pH (Even small amounts of B12 taken in supplements bypasses these steps, and thus, any need for gastric acid, which may be blocked by antacid drugs). Once the B12 is freed from the proteins in food, R-proteins, such as haptocorrins and cobalaphilins, are secreted, which bind to free vitamin B12 to form a B12-R complex. Also in the stomach, IF, a protein synthesized by gastric parietal cells, is secreted in response to histamine, gastrin and pentagastrin, as well as the presence of food. If this step fails due to gastric parietal cell atrophy (the problem in pernicious anemia), sufficient B12 is not absorbed later on, unless administered orally in relatively massive doses (500 to 1000 mcg/day). 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.
In the duodenum, proteases digest R-proteins and release B12, which then binds to IF, to form a B12-IF complex. B12 must be attached to IF for it to be absorbed, as receptors on the enterocytes in the terminal ileum only recognize the B12-IF complex, in addition, intrinsic factor protects the vitamin from catabolism by intestinal bacteria. The conjugated vitamin B12-intrinsic factor complex (IF/B12) is normally absorbed by the terminal ileum of the small bowel. Therefore, absorption of food vitamin B12 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.
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 of the vitamin. Genetic deficiencies of this protein are known, also leading to functional B12 deficiency.
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).
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.
Individuals who lack intrinsic factor have a decreased ability to absorb B12. This results in 80-100% excretion of oral doses in the feces versus 30-60% excretion in feces as seen in individuals with adequate intrinsic factor.
The total amount of vitamin B12 stored in body is about 2,000-5,000 mcg 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, however, most of the B12 that is secreted in the bile is recycled via enterohepatic circulation. Due to the extremely efficient enterohepatic circulation of B12, the liver can store several 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.
B12 deficiency is the cause of pernicious anemia, a usually-fatal disease of unknown etiology when it was first described in medicine. The cure was discovered by accident. George Whipple had been inducing anemia in dogs by bleeding them, and then conducting experiments in which he fed them various foods to observe which diets allowed them fastest recovery from the anemia produced. In the process, he discovered that ingesting large amounts of liver seemed to most-rapidly cure the anemia of blood loss, and hypothesized that therefore liver ingestion be tried for pernicious anemia, an anemic disease of the time with no known cause or cure. He tried this and reported some signs of success in 1920. After a series of careful clinical studies George Minot and William Murphy set out to partly isolate the substance in liver which cured anemia in dogs, and found that it was iron. They found further that the partly isolated water-soluble liver-substance which cured pernicious anemia in humans was something else entirely different—and which had no effect at all on canines under the conditions used. The specific factor treatment for pernicious anemia, found in liver juice, had been found by this coincidence. These experiments were reported by Minot and Murphy in 1926, marking the date of the first real progress with this disease, though for several years, patients were still required to eat large amounts of raw liver or to drink considerable amounts of liver juice.
In 1928, the chemist Edwin Cohn prepared a liver extract that was 50 to 100 times more potent than the natural liver products. The extract was the first workable treatment for the disease. For their initial work in pointing the way to a working treatment, Whipple, Minot, and Murphy shared the 1934 Nobel Prize in Physiology or Medicine.
The active ingredient in liver was not isolated until 1948 by the chemists Karl A. Folkers of the United States and Alexander R. Todd of Great Britain. The substance was a cobalamin called vitamin B12. It could also be injected directly into muscle, making it possible to treat pernicious anemia more easily.
The chemical structure of the molecule was determined by Dorothy Crowfoot Hodgkin and her team in 1956, based on crystallographic data. Eventually, methods of producing the vitamin in large quantities from bacteria cultures were developed in the 1950s, and these led to the modern form of treatment for the disease.
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, depression, and poor memory may be experienced. However, these symptoms by themselves are too nonspecific to diagnose deficiency of the vitamin.
Vitamin B12 deficiency has the following pathomorphology and symptoms:
Pathomorphology includes: A spongiform state of neural tissue along with edema of fibers and deficiency of tissue. The myelin decays, along with axial fiber. In later phases, fibric sclerosis of nervous tissues occurs. Those changes apply to dorsal parts of the spinal cord, and to pyramidal tracts in lateral cords. The pathophysiologic state of the spinal cord is called subacute combined degeneration of spinal cord.
In the brain itself, changes are less severe: they occur as small sources of nervous fibers decay and accumulation of astrocytes, usually subcortically located, an also round hemorrhages with a torus of glial cells. Pathological changes can be noticed as well in the posterior roots of the cord and, to lesser extent, in peripheral nerves.
Clinical symptoms : The main syndrome of vitamin B12 deficiency is Biermer's disease (pernicious anemia). It is characterized by a triad of symptoms:
Each of those symptoms can occur either alone or along with others. The neurological complex, defined as myelosis funicularis, consists of the following symptoms:
During the course of disease, mental disorders can occur which include: irritability, focus/concentration problems, depressive state with suicidal tendencies, paraphrenia complex. These symptoms may not reverse after correction of hematological abnormalities, and the chance of complete reversal decreases with the length of time the neurological symptoms have been present.
Vitamin B12 is naturally found in meat (especially liver and shellfish), milk and eggs. Animals, in turn, must obtain it directly or indirectly from bacteria, and these bacteria may inhabit a section of the gut which is posterior to the section where B12 is absorbed. Thus, herbivorous animals must either obtain B12 from bacteria in their rumens, or (if fermenting plant material in the hindgut) by reingestion of cecotrope fæces. Eggs are often mentioned as a good B12 source, but they also contain a factor that blocks absorption. Certain insects such as termites contain B12 produced by their gut bacteria, in a manner analogous to ruminant animals. An NIH Fact Sheet lists a variety of food sources of vitamin B12.
According to the U.K. Vegan Society, the present consensus is that any B12 present in plant foods is likely to be unavailable to humans and so these foods should not be relied upon as safe sources, as the B12 analogues can compete with B12 and inhibit metabolism. Also, vegan humans who eat only plant based foods must ordinarily take special care to supplement their diets accordingly. The only reliable vegan sources of B12 are foods fortified with B12 (including some soy products and some breakfast cereals), and B12 supplements. People on a vegan raw food diet are also susceptible to B12 deficiency if no supplementation is used. Brewer's yeast does not contain vitamin B12, an essential vitamin found in meat and dairy products; vegetarians sometimes take brewer's yeast mistakenly believing that it provides B12, which can be lacking in their diet.
While lacto-ovo vegetarians usually get enough B12 through consuming dairy products, vitamin B12 may be found to be lacking in those practicing vegan diets who do not use multivitamin supplements or eat B12 fortified foods. Examples of fortified foods often consumed include fortified breakfast cereals, fortified soy-based products, and fortified energy bars.
Vitamin B12 is found in foods that come from animals, including fish, meat, poultry, eggs, milk, and milk products. One half chicken breast provides some .3 µg per serving or 6.0% of one's daily value (DV), 3 ounces of beef, 2.4 µg, or 40% of one's DV, one slice of liver 47.9 µg or 780% of DV, and 3 ounces of molluscs 84.1 µg, or 1,400 % of DV, while one egg provides .6 µg or 10% of DV.
The mushroom Agaricus bisporus could contain Vitamin B12. This can be seen on some nutrition sites. Some sources say it is a form that is not usable as a Vitamin B12 source.
Legumes have root nodules that contain Rhizobia. These bacteria can create Vitamin B12. It may not be a source of Vitamin B12 for nutrition purposes.
Vitamin B12 is provided as a supplement in many processed foods, and is also available in vitamin pill form, including multi-vitamins. Vitamin B12 can be supplemented in healthy subjects also by liquid, transdermal patch, nasal spray, or injection and is available singly or in combination with other supplements.
The sublingual route, in which B12 is presumably or supposedly absorbed more directly under the tongue, has not proven to be necessary or helpful. A 2003 study found no significant difference in absorption for serum levels from oral vs. sublingual delivery of 500 µg (micrograms) of cobalamin. . Sublingual methods of replacement are effectively only because of the typically high doses (500 micrograms), which are swallowed, not because of placement of the tablet. As noted below, such very high doses of oral B12 may be effective as treatments, even if GI tract absorption is impaired by gastric atrophy (pernicious anemia).
Injection and patches are sometimes used in cases where digestive absorption is impaired, but there is evidence that this course of action may not be necessary with modern high potency oral supplements (such as 500 to 1000 µg or more). Even pernicious anemia can be treated entirely by the oral route. These supplements carry such large doses of the vitamin that 1% to 5% of high oral doses of free crystalline B12 is absorbed along the entire intestine by passive diffusion.
However, if the patient has inborn errors in the methyltransfer pathway (cobalamin C disease, combined methylmalonic aciduria and homocystinuria), treatment with intravenous, intramuscular hydroxocobalamin or transdermal B12 is needed.
Cyanocobalamin is also sometimes added to beverages including Diet Coke Plus and many energy drinks (one example would be Chaser's Five Hour Energy Drink, which contains 8333% of the Recommended Daily Value of Vitamin B12). However, 500 µg would be needed to reverse biochemical signs of vitamin B12 deficiency in older adults.
The Dietary Reference Intake for an adult ranges from 2 to 3 µg (micrograms) per day.
Vitamin B12 is believed to be safe when used orally in amounts that do not exceed the recommended dietary allowance (RDA). The RDA for vitamin B12 in pregnant women is 2.6 µg per day and 2.8 µg during lactation periods. There is insufficient reliable information available about the safety of consuming greater amounts of Vitamin B12 during pregnancy.
The Vegan Society, the Vegetarian Resource Group, and the Physicians Committee for Responsible Medicine, among others, recommend that vegans either consistently eat foods fortified with B12 or take a daily or weekly B12 supplement. Fortified breakfast cereals are a particularly valuable source of vitamin B12 for vegetarians and vegans. In addition, adults age 51 and older are recommended to consume B12 fortified food or supplements to meet the RDA, because they are a population at an increased risk of deficiency .
Vitamin B12 supplements in theory should be avoided in people sensitive or allergic to cobalamin, cobalt, or any other product ingredients. However, direct allergy to a vitamin or nutrient is extremely rare, and if reported, other causes should be sought.
Hydroxycobalamin, or hydoxocobalamin, also known as Vitamin B12a, is used in Europe both for vitamin B12 deficiency and as a treatment for cyanide poisoning, sometimes with a large amount (5-10 g) given intravenously, and sometimes in combination with sodium thiosulfate. 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 (in 2006) the use of hydroxocobalamin for acute treatment of cyanide poisoning.
Vitamin B12 enhances the phase-response of circadian melatonin rhythm to a single bright light exposure in humans. Sleep disturbances may occur because B12 may be involved in the regulation of the sleep wake cycle by the pineal gland (through melatonin).