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Vitamin B12
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Systematic (IUPAC) name | |
α-(5,6-dimethylbenzimidazolyl)cobamidcyanide | |
Identifiers | |
CAS number | |
ATC code | B03 |
PubChem | |
DrugBank | |
ChemSpider | |
Chemical data | |
Formula | C63H88CoN14O14P |
Mol. mass | 1355.37 g/mol |
Pharmacokinetic data | |
Bioavailability | readily absorbed in lower half ileum |
Protein binding | Very high to specific transcobalamins plasma proteins Binding of hydroxocobalamin is slightly higher than cyanocobalamin. |
Metabolism | hepatic |
Half life | Approximately 6 days (400 days in the liver) |
Excretion | renal |
Therapeutic considerations | |
Pregnancy cat. |
? |
Legal status |
POM(UK) |
Routes | oral, iv |
Vitamin B-12 is one of eight B vitamins which is important for the normal functioning of the brain and nervous system, and for the formation of blood. 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 B-12 is the name for a class of chemically-related compounds, all of which have vitamin activity. It is structurally the most complicated vitamin. 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 B-12 was discovered from its relationship to the disease pernicious anemia, which was eventually discovered to result from an effective lack of this vitamin due to problems with the mechanisms in the body which normally absorb it. Many other subtler kinds of vitamin B12 deficiency, and their biochemical effects, have since been elucidated.
The name vitamin B-12, known as vitamin B12 (commonly B12 or B-12 for short) 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-B-12 refers to B-12-like substances which are found in certain organisms, including Spirulina (a cyanobacterium) and some algae. These substances are active in tests of B-12 activity by highly sensitive antibody-binding serum assay tests, which measure levels of B-12 and B-12-like compounds in blood. However, these substances do not have B-12 biological activity for humans, a fact which may pose a danger to vegans and others on limited diets who do not ingest B-12 producing bacteria, but who nevertheless may show normal "B-12" levels in the standard immunoassay which has become the normal medical method for testing for B-12 deficiency.[2]
Vitamin B-12 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 B-12 is made must be synthesized by bacteria. However, after this synthesis is complete, the body has a limited power to convert any form of B-12 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 B-12 does not occur in nature normally, but is a byproduct of the fact that other forms of B-12 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 B-12 is deeply red colored, easy to crystallize, and is not sensitive to air-oxidation, it is typically used as a form of B-12 for food additives and in many common multivitamins. However, this form is not perfectly synonymous with B-12, inasmuch as a number of substances (vitamers) have B-12 vitamin activity and can properly be labeled vitamin B-12, and cyanocobalamin is but one of them. (Thus, all cyanocobalamin is vitamin B-12, but not all vitamin B-12 is cyanocobalamin).[3]
B-12 is the most chemically complex of all the vitamins. The structure of B-12 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 B-12 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.[4]
Vitamin B-12 cannot be made by plants or animals[5] as only bacteria have the enzymes required for its synthesis. The total synthesis of B-12 was reported by Robert Burns Woodward[6] and Albert Eschenmoser,[7][8] and remains one of the classic feats of organic synthesis.
Species from the following genera are known to synthesize B-12: Aerobacter, Agrobacterium, Alcaligenes, Azotobacter, Bacillus, Clostridium, Corynebacterium, Flavobacterium, Micromonospora, Mycobacterium, Nocardia, Propionibacterium, Protaminobacter, Proteus, Pseudomonas, Rhizobium, Salmonella, Serratia, Streptomyces, Streptococcus and Xanthomonas. Industrial production of B-12 is through fermentation of selected microorganisms.[9] The species most often used, Pseudomonas denitrificans and Propionibacterium shermanii, are frequently genetically engineered and grown under special conditions to enhance yield.
Vitamin B-12 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 B-12 can be replaced by sufficient quantities of folic acid (another B vitamin), since B-12 is used to regenerate folate in the body. Most "B-12 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 B-12 related deficiency syndromes normalize, save those narrowly connected with the B-12 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 B-12's reactive C-Co bond participates in two types of enzyme-catalyzed reactions.[10]
In humans, only two corresponding coenzyme B-12-dependent enzymes are known:
If folate is present in quantity, then of the two absolutely B-12 dependent reactions, the MUT reaction shows the most direct and characteristic secondary effects, focusing on the nervous system. 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 B-12 deficiency are becoming apparent not as anemia (as they were classically), but now mainly as an 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 is difficult to separate from other processes associated with atherosclerosis and aging.
The B-12 dependent MTR reactions may have neurological effects through an indirect mechanism. Adequate methionine (which must otherwise be obtained in the diet) is needed to make S-adenosyl-methionine, which is in turn necessary for methylation of myelin sheath phospholipids. 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 B-12 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 B-12 deficiency has also been connected to B-12 reactions related to MUT, which is needed 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.[14] Whatever the cause, it is known that B-12 deficiency causes neuropathies, even if folic acid is present in good supply, and therefore anemia is not present.
The human physiology of vitamin B-12 is complex, and therefore is prone to mishaps leading to vitamin B-12 deficiency. The vitamin as it occurs in foods enters the digestive tract bound to proteins, known as salivary R-binders. Stomach proteolysis of these proteins requires an acid pH, and also requires proper pancreatic release of proteolytic enzymes referred to as pepsin. (Even small amounts of B-12 taken in supplements bypasses these steps and thus any need for gastric acid, which may be blocked by antacid drugs).
The free B-12 then attaches to gastric intrinsic factor, which is generated by the gastric parietal cells in response to histamine, gastrin and pentagastrin, as well as the presence of food. The generation of this intrinsic factor-B12 complex will allow absorption of the vitamin as well as protect the vitamin from catabolism by intestinal bacteria. If this step fails due to gastric parietal cell atrophy (the problem in pernicious anemia), sufficient B-12 is not absorbed later on, unless administered orally in relatively massive doses (500 to 1000 mcg/day). Due to the complexity of B-12 absorption, geriatric patients, many of whom are hypoacidic due to reduced parietal cell function, have an increased risk of B-12 deficiency.[15]
The conjugated vitamin B-12-intrinsic factor complex (IF/B-12) is then normally absorbed by the terminal ileum of the small bowel. Absorption of food vitamin B-12 therefore requires an intact and functioning stomach, exocrine pancreas, intrinsic factor, and small bowel. Problems with any one of these organs makes a vitamin B-12 deficiency possible.
Once the IF/B-12 complex is recognized by specialized ileal receptors, it is transported into the portal circulation. The vitamin is then transferred to transcobalamin II (TC-II/B-12), which serves as the plasma transporter of the vitamin. Genetic deficiencies of this protein are known, also leading to functional B-12 deficiency.
For the vitamin to serve inside cells, the TC-II/B-12 complex must bind to a cell receptor, and be endocytosed. The transcobalamin-II is degraded within a lysozyme, and free B-12 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 B-12 and infantile megaloblastic anemia, and abnormal B-12 related biochemistry, even in some cases with normal blood B-12 levels.[16]
Individuals who lack intrinsic factor have a decreased ability to absorb B-12. 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.[15]
The total amount of vitamin B-12 stored in body is about 2,000-5,000 mcg in adults. Around 80% of this is stored in the liver[17]. Approximately 0.1% of this is lost per day by secretions into the gut as not all these secretions are reabsorbed. How fast B-12 levels change depends on the balance between how much B-12 is obtained from the diet, how much is secreted and how much is absorbed. B-12 deficiency may arise in a year if initial stores are low and genetic factors unfavourable or may not appear for decades. In infants, B-12 deficiency can appear much more quickly[18].
B-12 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 B-12. It could also be injected directly into muscle, making it possible to treat pernicious anemia more easily.[19]
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 B-12 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.[20] However, these symptoms by themselves are too nonspecific to diagnose deficiency of the vitamin.
Vitamin B-12 deficiency can also cause symptoms of mania and psychosis.[21][22]
Vitamin B-12 deficiency has the following pathomorphology and symptoms:[23]
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.
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 B-12 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 B-12 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 B-12 is absorbed. Thus, herbivorous animals must either obtain B-12 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 B-12 source, but they also contain a factor that blocks absorption.[24] Certain insects such as termites contain B-12 produced by their gut bacteria, in a manner analogous to ruminant animals.[25] An NIH Fact Sheet lists a variety of food sources of vitamin B-12.
Plants do not supply B-12 to humans. Vegan humans who eat only plant based foods must ordinarily take special care to supplement their diets accordingly. According to the U.K. Vegan Society, the only reliable vegan sources of B-12 are foods fortified with B-12 (including some soy products and some breakfast cereals), and B-12 supplements.[26]
While lacto-ovo vegetarians usually get enough B-12 through consuming dairy products, vitamin B-12 may be found to be lacking in those practicing vegan diets who do not use multivitamin supplements or eat B-12 fortified foods. Examples of fortified foods often consumed include fortified breakfast cereals, fortified soy-based products, and fortified energy bars. Claimed sources of B-12 that have been shown through direct studies[27] of vegans to be inadequate or unreliable include, laver (a seaweed), barley grass, and human gut bacteria. People on a vegan raw food diet are also susceptible to B-12 deficiency if no supplementation is used[28].
Vitamin B12 is found in foods that come from animals, including fish, meat, poultry, eggs, milk, and milk products.[29] One half chicken breast, provides some .3 µg per serving or 6.0% of your daily value, (DV) 3 ounces of beef, 2.4 µg, or 40% of your DV, one slice of liver 47.9 µg or 780% of your DV, and 3 ounces of Molluscs 84.1 µg, or 1,400 % of your DV, while one egg provides .6 µg or 10% of your DV. Vegetarians have a challenge to ensure that they meet their daily allowance for B-12.
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 B-12 or take a daily or weekly B-12 supplement.[26][30][31] Fortified breakfast cereals are a particularly valuable source of vitamin B-12 for vegetarians and vegans.
Cyanocobalamin is converted to its active forms, first hydroxocobalamin and then methylcobalamin and adenosylcobalamin in the liver.
Vitamin B-12 can be supplemented in healthy subjects also by liquid, strip, nasal spray, or injection and is available singly or in combination with other supplements.
The sublingual route, in which B-12 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.[32]
Injection is sometimes used in cases where digestive absorption is impaired, but there is some 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.[33][34][35] These supplements carry such large doses of the vitamin that the many different components of the B-12 absorption system are not required, and enough of the vitamin (only a few µg a day) is obtained simply by mass-action transport across the gut.
However, if the patient has inborn errors in the methyltransfer pathway (cobalamin C disease, combined methylmalonic aciduria and homocystinuria), treatment with intravenous or intramuscular hydroxocobalamin is needed.[36][37][38][39][40]
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 B-12[41].) However, 500 µg would be needed to reverse biochemical signs of vitamin B-12 deficiency in older adults.[42]
The Dietary Reference Intake for an adult ranges from 2 to 3 µg (micrograms) per day.
Vitamin B-12 is believed to be safe when used orally in amounts that do not exceed the recommended dietary allowance (RDA). The RDA for vitamin B-12 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 B-12 during pregnancy.
Vitamin B-12 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 B-12a, is used in Europe both for vitamin B-12 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.[44] The mechanism of action is straightforward: the hydroxycobalamin hydroxide ligand is displaced by the toxic cyanide ion, and the resulting harmless B-12 complex is excreted in urine. In the United States, the FDA approved (in 2006) the use of hydroxocobalamin for acute treatment of cyanide poisoning.
High vitamin B12 level in elderly individuals may protect against brain atrophy or shrinkage, associated with Alzheimer's disease and impaired cognitive function.[45]
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