Vitamin B12
Encyclopedia
Vitamin B12, vitamin B12 or vitamin B-12, also called cobalamin, 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 human body, especially affecting DNA
synthesis and regulation, but also fatty acid
synthesis and energy production. It is the largest and most structurally complicated vitamin and can be produced industrially only through bacterial fermentation-synthesis.
Vitamin B12 consists of a class of chemically-related compounds (vitamer
s), all of which have vitamin activity. It contains the biochemically rare element cobalt
. Biosynthesis
of the basic structure of the vitamin in nature is only accomplished by simple organisms such as some bacteria
and algae, 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 and supplements, and as a food additive, because of 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
(a form produced by bacteria), methylcobalamin, and adenosylcobalamin can also be found in more expensive pharmacological products and food supplements. The extra utility of these is currently debated.
Vitamin B12 was discovered from its relationship to the disease pernicious anemia
, which is an autoimmune disease
in which parietal cell
s of the stomach responsible for secreting intrinsic factor
are destroyed. Intrinsic factor is crucial for the normal absorption of B12, so 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.
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 diets who may not ingest sufficient quantities of B12 producing bacteria, but who nevertheless may show normal "B12" levels in the standard immunoassay which has become the normal medical method for testing for B12 deficiency.
, cyanide poisoning
, and hereditary deficiency of transcobalamin II. It is also given as part of the schilling test
for detecting pernicious anemia
.
For cyanide
poisoning, a large amount 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 (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.
High-dose administration of Vitamin B12 has been additionally validated to stimulate the activity of the body's TH1 suppressor T-Cells, which then down-regulates the over-production of the allergen antibody IgE in allergic individuals...
for an adult ranges from 2 to 3 µg per day.
Vitamin B12 is believed to be safe when used orally in amounts that do not exceed the recommended dietary allowance (RDA). There have also been studies that showed no adverse consequences of doses above the 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 cereal
s 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.
, and poor memory
may be experienced. However, these symptoms by themselves are too nonspecific to diagnose deficiency of the vitamin.
Vitamin B12 deficiency can also cause symptoms of mania and psychosis. Vitamin B12 deficiency can be caused by the metabolic disorder pernicious anemia
.
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.
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. The various forms (vitamer
s) of B12 are all deeply red colored, due to the color of the cobalt-corrin complex.
Cyanocobalamin
is one such "vitamer
" in this B complex
, because it can be metabolized in the body to an 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 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, in as much as a number of substances (vitamer
s) 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).
Pure cyanocoblamin possesses the deep pink colour associated with most octahedral cobalt(II) complexes and the crystals are well formed and easily grown up to millimetre size.
Hydroxocobalamin
is another form of B12 commonly encountered in pharmacology, but which is not normally present in the human body. Hydroxocobalamin is sometimes denoted B12a. This form of B12 is the form produced by bacteria, and is what is converted to cyanocobalmin in the commercial charcoal filtration step of production. Hydroxocobalamin has an avid affinity for cyanide
ion and has been used as an antidote to cyanide poisoning. It is supplied typically in water solution for injection. Hydroxocobalamin is thought to be converted to the active enzymic forms of B12 more easily than cyanocobalamin, and since it is little more expensive than cyanocobalamin, and has 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.
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 hydrogenase
s and, by necessity, enzymes associated with cobalt utilization, involve metal-carbon bonds.
have the enzymes required for its synthesis. The total synthesis of B12
was reported by Robert Burns Woodward
and Albert Eschenmoser
in 1972, and remains one of the classic feats of organic synthesis. Species from the following genera
are known to synthesize B12: Acetobacterium
, 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
, which has merged into Sanofi-Aventis
, used genetically engineered versions of one or both of these species. Since a number of species of Propionibacterium
produce no exotoxin
s or endotoxin
s and are generally regarded as safe (have been granted GRAS
status) by the Food and Drug Adminstration of the United States, they are presently the FDA-preferred bacterial fermentation organisms for vitamin B12 production.
The total world production of vitamin B12, by four companies (the French Sanofi-Aventis and three Chinese companies) is said to have been 35 tonnes in 2008. Most of this production is used as an additive to animal feed.
Vitamin B12 normally plays a significant role 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
(vitamin B9), since B12 is used to regenerate folate in the body. Most vitamin B12 deficiency symptoms are actually folate deficiency 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 vitamin B12-dependent enzymes Methylmalonyl Coenzyme A mutase, 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 three main types of enzyme-catalyzed reactions.
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:
-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 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.
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.
. 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. In addition some elderly people produce less stomach acid as they age thereby increasing their probability of B12 deficiencies.
B12 taken in a low-solubility, non-chewable supplement pill form may bypass the mouth and stomach and not mix with gastric acids, but these are not necessary for the absorption of free B12 not bound to protein.
R-proteins (such as haptocorrin
s and cobalaphilin) are B12 binding proteins that are produced in the salivary glands. They must wait until B12 has been freed from proteins in food by pepsin
in the stomach. B12 then binds to the R-Proteins to avoid degradation of it in the acidic environment of the stomach.
This pattern of secretion of a binding protein secreted in a previous digestive step, is repeated once more before absorption. The next binding protein is intrinsic factor (IF), a protein synthesized by gastric parietal cell
s that is secreted in response to histamine
, gastrin
and pentagastrin
, as well as the presence of food.
In the duodenum
, protease
s digest R-proteins and release B12, which then binds to IF, to form a complex (IF/B12). B12 must be attached to IF for it to be 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).
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; however, most of the B12 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.
, an anemic disease that was usually fatal and had unknown etiology when it was first described in medicine. The cure, and B12, were discovered by accident. George Whipple
had been doing experiments in which he induced anemia
in dogs by bleeding them, and then 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. Thus, he hypothesized that liver ingestion might treat pernicious anemia. He tried this and reported some signs of success in 1920.
After a series of careful clinical studies, George Richards Minot and William Murphy
set out to partly isolate the substance in liver which cured anemia in dogs, and found that it was iron
. They also found that an entirely different liver substance cured pernicious anemia in humans, that had no effect on dogs under the conditions used. The specific factor treatment for pernicious anemia, found in liver juice, had been found by this coincidence. Minot and Murphy reported these experiments in 1926. This was the first real progress with this disease. Despite this discovery, for several years patients were still required to eat large amounts of raw liver or to drink considerable amounts 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
.
These events in turn eventually led to discovery of the soluble vitamin, called vitamin B12, in the liver juice. The vitamin in liver extracts was not isolated until 1948 by the contributions of chemists Mary Shaw Shorb and Karl A. Folkers of the United States and Alexander R. Todd of Great Britain. In 1947, while working for the Poultry Science Department at the University of Maryland, Mary Shorb (in a collaborative project with Folkers and Merck) was provided with a $400 grant to develop the LLD assay. The LLD assay led to the purification and characterization of Vitamin B12 as it caused rapid isolation of the anti-pernicious anemia factor. For this discovery, in 1949 Mary Shorb and Karl Folkers received the Mead Johnson Award from the American Society of Nutritional Sciences.
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.
Ultimately, animals must obtain vitamin B12 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 rumen
s, or (if fermenting plant material in the hindgut
) by reingestion of cecotrope fæces.
Vitamin B12 is found in foods that come from animals, including fish and shellfish
, meat (especially liver
), poultry
, eggs, milk, and milk products. Egg
s are often mentioned as a good B12 source, but they also contain a factor that blocks absorption. However, the binding capacity of heat treated egg yolks and egg whites is markedly diminished after heat treatment. Certain insects such as termites contain B12 produced by their gut bacteria, in a way analogous to ruminant animals. An NIH Fact Sheet lists a variety of food sources of vitamin B12.
While lacto-ovo vegetarians usually get enough B12 through consuming dairy product
s, vegan
s will lack B12 unless they consume B12-containing dietary supplements or B12-fortified foods.
Examples of fortified foods
include fortified breakfast cereals, fortified soy
products, fortified energy bar
s, and fortified nutritional yeast
. According to the UK Vegan Society
, the present consensus is that any B12 present in plant foods is likely to be unavailable to humans because B12 analogues can compete with B12 and inhibit metabolism
.
Claimed sources of B12 that have been shown to be inadequate or unreliable through direct studies of vegans include laver
(a seaweed
), barley
grass, and human intestinal bacteria (human colonic bacteria produce B12, but it cannot be absorbed from the colon).
s and energy shot
s, usually at several times the minimum recommended daily allowance of B12.
Cyanocobalamin
is converted to its active forms, first hydroxocobalamin
and then methylcobalamin and adenosylcobalamin in the liver.
The sublingual route, in which B12 is presumably or supposedly absorbed more directly under the tongue, has not proven to be necessary or helpful, though there are a number of lozenges, pills, and even a lollipop designed for sublingual absorption. A 2003 study found no significant difference in absorption for serum levels from oral vs. sublingual delivery of 0.5 mg of cobalamin. Sublingual methods of replacement are effective only because of the typically high doses (0.5 mg), 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 gastro-intestinal tract absorption is impaired by gastric atrophy (pernicious anemia).
Injection and patches are sometimes used if digestive absorption is impaired, but there is evidence that this course of action may not be necessary with modern high potency oral supplements (such as 0.5 to 1 mg 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.
is released with methylcobolamin, although the amount of cyanide (2% of the weight, or 20 micrograms cyanide in a 1 mg cyanocobalamin tab) is far less than ingested in many natural foods. Although the safety of cyanocobalamin has not been seriously questioned, the safety of the other types is also well-established.
Vitamin
A vitamin is an organic compound required as a nutrient in tiny amounts by an organism. In other words, an organic chemical compound is called a vitamin when it cannot be synthesized in sufficient quantities by an organism, and must be obtained from the diet. Thus, the term is conditional both on...
with a key role in the normal functioning of the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
and nervous system
Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
, and for the formation of blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
. It is one of the eight B vitamins
B vitamins
B vitamins are a group of water-soluble vitamins that play important roles in cell metabolism. The B vitamins were once thought to be a single vitamin, referred to as vitamin B . Later research showed that they are chemically distinct vitamins that often coexist in the same foods...
. It is normally involved in the metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
of every cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
of the human body, especially affecting DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
synthesis and regulation, but also fatty acid
Fatty acid
In chemistry, especially biochemistry, a fatty acid is a carboxylic acid with a long unbranched aliphatic tail , which is either saturated or unsaturated. Most naturally occurring fatty acids have a chain of an even number of carbon atoms, from 4 to 28. Fatty acids are usually derived from...
synthesis and energy production. It is the largest and most structurally complicated vitamin and can be produced industrially only through bacterial fermentation-synthesis.
Vitamin B12 consists of a class of chemically-related compounds (vitamer
Vitamer
A vitamer of a particular vitamin is any of a number of chemical substances, each of which shows vitamin activity. Very commonly each "vitamin" is not a single chemical, but rather multiple chemical substances called vitamers, each of which is defined by its different biological activity.For...
s), all of which have vitamin activity. It contains the biochemically rare element cobalt
Cobalt
Cobalt is a chemical element with symbol Co and atomic number 27. It is found naturally only in chemically combined form. The free element, produced by reductive smelting, is a hard, lustrous, silver-gray metal....
. Biosynthesis
Biosynthesis
Biosynthesis is an enzyme-catalyzed process in cells of living organisms by which substrates are converted to more complex products. The biosynthesis process often consists of several enzymatic steps in which the product of one step is used as substrate in the following step...
of the basic structure of the vitamin in nature is only accomplished by simple organisms such as some bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
and algae, but conversion between different forms of the vitamin can be accomplished in the human body. A common synthetic form of the vitamin, cyanocobalamin
Cyanocobalamin
Cyanocobalamin is an especially common vitamer of the vitamin B12 family. It is the most famous vitamer of the family, because it is, in chemical terms, the most air-stable...
, does not occur in nature, but is used in many pharmaceuticals and supplements, and as a food additive, because of its stability and lower cost. In the body it is converted to the physiological forms, methylcobalamin and adenosylcobalamin, leaving behind the cyanide
Cyanide
A cyanide is a chemical compound that contains the cyano group, -C≡N, which consists of a carbon atom triple-bonded to a nitrogen atom. Cyanides most commonly refer to salts of the anion CN−. Most cyanides are highly toxic....
, albeit in minimal concentration. More recently, hydroxocobalamin
Hydroxocobalamin
Hydroxocobalamin is a natural form, or vitamer, of vitamin B12, a basic member of the cobalamin family of compounds. Hydroxocobalamin is the form of vitamin B12 produced by many bacteria which are used to produce the vitamin commercially. Like other forms of vitamin B12, hydroxocobalamin has an...
(a form produced by bacteria), methylcobalamin, and adenosylcobalamin can also be found in more expensive pharmacological products and food supplements. The extra utility of these is currently debated.
Vitamin B12 was discovered from its relationship to the disease pernicious anemia
Pernicious anemia
Pernicious anemia is one of many types of the larger family of megaloblastic anemias...
, which is an autoimmune disease
Autoimmune disease
Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...
in which parietal cell
Parietal cell
Parietal cells, or oxyntic cells, are the stomach epithelium cells that secrete gastric acid and intrinsic factor.Acetylcholine and gastrin . The histamine receptors act by increasing intracellular cAMP, whereas the muscarinic and gastrin receptors increase intracellular Ca2+ levels...
s of the stomach responsible for secreting intrinsic factor
Intrinsic factor
Intrinsic factor also known as gastric intrinsic factor is a glycoprotein produced by the parietal cells of the stomach. It is necessary for the absorption of vitamin B12 later on in the small intestine...
are destroyed. Intrinsic factor is crucial for the normal absorption of B12, so a lack of intrinsic factor, as seen in pernicious anemia, causes a vitamin B12 deficiency
Vitamin B12 deficiency
Vitamin B12 deficiency or hypocobalaminemia is a low blood level of vitamin B12, it can cause permanent damage to nervous tissue as a long term effect. Vitamin B12 was discovered from its relationship to the disease pernicious anemia, which is an autoimmune disease that destroys parietal cells in...
. Many other subtler kinds of vitamin B12 deficiency and their biochemical effects have since been elucidated.
Terminology
The names vitamin B, vitamin B12, or vitamin B-12, and the alternative name cobalamin, generally refer to all forms of the vitamin. Some medical practitioners have suggested that its use be split into two different categories, however.- In a broad sense, B12 refers to a group of cobaltCobaltCobalt is a chemical element with symbol Co and atomic number 27. It is found naturally only in chemically combined form. The free element, produced by reductive smelting, is a hard, lustrous, silver-gray metal....
-containing vitamerVitamerA vitamer of a particular vitamin is any of a number of chemical substances, each of which shows vitamin activity. Very commonly each "vitamin" is not a single chemical, but rather multiple chemical substances called vitamers, each of which is defined by its different biological activity.For...
compounds known as cobalamins: these include cyanocobalaminCyanocobalaminCyanocobalamin is an especially common vitamer of the vitamin B12 family. It is the most famous vitamer of the family, because it is, in chemical terms, the most air-stable...
(an artifact formed from using activated charcoal, which always contains trace cyanideCyanideA cyanide is a chemical compound that contains the cyano group, -C≡N, which consists of a carbon atom triple-bonded to a nitrogen atom. Cyanides most commonly refer to salts of the anion CN−. Most cyanides are highly toxic....
, to purify hydroxycobalamin), hydroxocobalaminHydroxocobalaminHydroxocobalamin is a natural form, or vitamer, of vitamin B12, a basic member of the cobalamin family of compounds. Hydroxocobalamin is the form of vitamin B12 produced by many bacteria which are used to produce the vitamin commercially. Like other forms of vitamin B12, hydroxocobalamin has an...
(another medicinal form, produced by bacteria), and finally, the two naturally occurring cofactorCofactor (biochemistry)A cofactor is a non-protein chemical compound that is bound to a protein and is required for the protein's biological activity. These proteins are commonly enzymes, and cofactors can be considered "helper molecules" that assist in biochemical transformations....
forms of B12 in the human body: 5'-deoxyadenosylcobalamin (adenosylcobalamin—AdoB12), the cofactor of Methylmalonyl Coenzyme A mutase (MUT), and methylcobalamin (MeB12), the cofactor of 5-methyltetrahydrofolate-homocysteine methyltransferase5-methyltetrahydrofolate-homocysteine methyltransferaseMethionine synthase also known as MS, MeSe, MetH is an enzyme that in humans is encoded by the MTR gene . This enzyme is responsible for the regeneration of methionine from homocysteine...
(MTR5-methyltetrahydrofolate-homocysteine methyltransferaseMethionine synthase also known as MS, MeSe, MetH is an enzyme that in humans is encoded by the MTR gene . This enzyme is responsible for the regeneration of methionine from homocysteine...
). - The term B12 may be properly used to refer to cyanocobalaminCyanocobalaminCyanocobalamin is an especially common vitamer of the vitamin B12 family. It is the most famous vitamer of the family, because it is, in chemical terms, the most air-stable...
, the principal B12 form used for foods and in nutritional supplements. This ordinarily creates no problem, except perhaps in rare cases of eye nerve damage, where the body is only marginally able to use this form due to high cyanide levels in the blood due to cigarette smoking, and thus requires cessation of smoking, or else B12 given in another form, for the optic symptoms to abate. However, tobacco amblyopiaAmblyopiaAmblyopia, also known as lazy eye, is a disorder of the visual system that is characterized by a vision deficiency in an eye that is otherwise physically normal, or out of proportion to associated structural abnormalities of the eye...
is a rare enough condition that debate continues about whether or not it represents a peculiar B12 deficiency which is resistant to treatment with cyanocobalamin.
Finally, so-called pseudo-B12 refers to B12-like substances which are found in certain organisms, including Spirulina
Spirulina (genus)
Spirulina is a genus of cyanobacteria. As a photosynthetic organism capable of fixing nitrogen, its non-protein nutrient values are relatively low. Spirulina is used in some foods for aquarium fish...
(a cyanobacterium) and some algae
Algae
Algae are a large and diverse group of simple, typically autotrophic organisms, ranging from unicellular to multicellular forms, such as the giant kelps that grow to 65 meters in length. They are photosynthetic like plants, and "simple" because their tissues are not organized into the many...
. 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
Veganism
Veganism is the practice of eliminating the use of animal products. Ethical vegans reject the commodity status of animals and the use of animal products for any purpose, while dietary vegans or strict vegetarians eliminate them from their diet only...
and others on diets who may not ingest sufficient quantities of B12 producing bacteria, but who nevertheless may show normal "B12" levels in the standard immunoassay which has become the normal medical method for testing for B12 deficiency.
Medical uses
Vitamin B12, is used to treat vitamin B12 deficiencyVitamin B12 deficiency
Vitamin B12 deficiency or hypocobalaminemia is a low blood level of vitamin B12, it can cause permanent damage to nervous tissue as a long term effect. Vitamin B12 was discovered from its relationship to the disease pernicious anemia, which is an autoimmune disease that destroys parietal cells in...
, cyanide poisoning
Cyanide poisoning
Cyanide poisoning occurs when a living organism is exposed to a compound that produces cyanide ions when dissolved in water. Common poisonous cyanide compounds include hydrogen cyanide gas and the crystalline solids potassium cyanide and sodium cyanide...
, and hereditary deficiency of transcobalamin II. It is also given as part of the schilling test
Schilling test
The Schilling test is a medical investigation used for patients with vitamin B deficiency. The purpose of the test is to determine whether the patient has pernicious anemia.It is named for Robert F. Schilling.-Process:The Schilling test has multiple stages...
for detecting pernicious anemia
Pernicious anemia
Pernicious anemia is one of many types of the larger family of megaloblastic anemias...
.
For cyanide
Cyanide
A cyanide is a chemical compound that contains the cyano group, -C≡N, which consists of a carbon atom triple-bonded to a nitrogen atom. Cyanides most commonly refer to salts of the anion CN−. Most cyanides are highly toxic....
poisoning, a large amount may be given intravenously, and sometimes in combination with sodium thiosulfate
Sodium thiosulfate
Sodium thiosulfate , also spelled sodium thiosulphate, is a colorless crystalline compound that is more familiar as the pentahydrate, Na2S2O3•5H2O, an efflorescent, monoclinic crystalline substance also called sodium hyposulfite or “hypo.”...
. The mechanism of action is straightforward: the hydroxycobalamin hydroxide ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
is displaced by the toxic cyanide ion, and the resulting harmless B12 complex is excreted in urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
. In the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
, the Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
approved (in 2006) the use of hydroxocobalamin for acute treatment of cyanide poisoning.
High vitamin B12 level in elderly individuals may protect against brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
atrophy
Atrophy
Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations , poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply to the target organ, disuse or lack of exercise or disease intrinsic to the tissue itself...
or shrinkage, associated with Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
and impaired cognitive function.
High-dose administration of Vitamin B12 has been additionally validated to stimulate the activity of the body's TH1 suppressor T-Cells, which then down-regulates the over-production of the allergen antibody IgE in allergic individuals...
Recommended intake
The dietary reference intakeDietary Reference Intake
The Dietary Reference Intake is a system of nutrition recommendations from the Institute of Medicine of the U.S. National Academy of Sciences. The DRI system is used by both the United States and Canada and is intended for the general public and health professionals...
for an adult ranges from 2 to 3 µg per day.
Vitamin B12 is believed to be safe when used orally in amounts that do not exceed the recommended dietary allowance (RDA). There have also been studies that showed no adverse consequences of doses above the RDA. The RDA for vitamin B12 in pregnant
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
women is 2.6 µg per day and 2.8 µg during lactation
Lactation
Lactation describes the secretion of milk from the mammary glands and the period of time that a mother lactates to feed her young. The process occurs in all female mammals, however it predates mammals. In humans the process of feeding milk is called breastfeeding or nursing...
periods. There is insufficient reliable information available about the safety of consuming greater amounts of vitamin B12 during pregnancy.
The Vegan Society
Vegan Society
The Vegan Society is a registered charity and the oldest vegan society in the world, founded on November 1, 1944, in England by Donald Watson, Elsie "Sally" Shrigley, and 23 others....
, the Vegetarian Resource Group, and the Physicians Committee for Responsible Medicine
Physicians Committee for Responsible Medicine
The Physicians Committee for Responsible Medicine is a non-profit organization based in Washington, D.C., which promotes a vegan diet, preventive medicine, alternatives to animal research, and encourages what it describes as "higher standards of ethics and effectiveness in research." Its primary...
, among others, recommend that vegans either consistently eat foods fortified with B12 or take a daily or weekly B12 supplement. Fortified breakfast cereal
Breakfast cereal
A breakfast cereal is a food made from processed grains that is often, but not always, eaten with the first meal of the day. It is often eaten cold, usually mixed with milk , water, or yogurt, and sometimes fruit but sometimes eaten dry. Some cereals, such as oatmeal, may be served hot as porridge...
s are a particularly valuable source of vitamin B12 for vegetarians
Vegetarianism
Vegetarianism encompasses the practice of following plant-based diets , with or without the inclusion of dairy products or eggs, and with the exclusion of meat...
and vegans
Veganism
Veganism is the practice of eliminating the use of animal products. Ethical vegans reject the commodity status of animals and the use of animal products for any purpose, while dietary vegans or strict vegetarians eliminate them from their diet only...
. 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.
Deficiency
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, depressionDepression (mood)
Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless...
, and poor memory
Memory
In psychology, memory is an organism's ability to store, retain, and recall information and experiences. Traditional studies of memory began in the fields of philosophy, including techniques of artificially enhancing memory....
may be experienced. However, these symptoms by themselves are too nonspecific to diagnose deficiency of the vitamin.
Vitamin B12 deficiency can also cause symptoms of mania and psychosis. Vitamin B12 deficiency can be caused by the metabolic disorder pernicious anemia
Pernicious anemia
Pernicious anemia is one of many types of the larger family of megaloblastic anemias...
.
Adverse effects
- Vitamin B12 has extremely low toxicity and even taking it in enormous doses appears not to be harmful to healthy individuals.
- Hematologic: Peripheral vascular thrombosis has been reported. Treatment of vitamin B12 deficiency can unmask polycythemia veraPolycythemia veraPolycythemia vera is a blood disorder in which the bone marrow makes too many red blood cells. It may also result in the overproduction of white blood cells and platelets. Most of the health concerns associated with polycythemia vera are caused by the blood being thicker as a result of the...
, which is characterized by an increase in blood volume and the number of red blood cells. The correction of megaloblastic anemiaMegaloblastic anemiaMegaloblastic anemia is an anemia that results from inhibition of DNA synthesis in red blood cell production. When DNA synthesis is impaired, the cell cycle cannot progress from the G2 growth stage to the mitosis stage...
with vitamin B12 can result in fatal hypokalemiaHypokalemiaHypokalemia or hypokalaemia , also hypopotassemia or hypopotassaemia , refers to the condition in which the concentration of potassium in the blood is low...
and goutGoutGout is a medical condition usually characterized by recurrent attacks of acute inflammatory arthritis—a red, tender, hot, swollen joint. The metatarsal-phalangeal joint at the base of the big toe is the most commonly affected . However, it may also present as tophi, kidney stones, or urate...
in susceptible individuals, and it can obscure folate deficiency in megaloblastic anemia. Caution is warranted. - Leber's disease: Vitamin B12 in the form of cyanocobalamin is contraindicated in early Leber's disease, which is hereditary optic nerveOptic nerveThe optic nerve, also called cranial nerve 2, transmits visual information from the retina to the brain. Derived from the embryonic retinal ganglion cell, a diverticulum located in the diencephalon, the optic nerve doesn't regenerate after transection.-Anatomy:The optic nerve is the second of...
atrophyAtrophyAtrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations , poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply to the target organ, disuse or lack of exercise or disease intrinsic to the tissue itself...
. Cyanocobalamin can cause severe and swift optic atrophy, but other forms of vitamin B12 are available. However, the sources of this statement are not clear, while an opposing view concludes: "The clinical picture of optic neuropathy associated with vitamin B12 deficiency shows similarity to that of Leber's disease optic neuropathy. Both involve the nerve fibres of the papillomacular bundle. The present case reports suggest that optic neuropathy in patients carrying a primary LHON mtDNA mutation may be precipitated by vitamin B12 deficiency. Therefore, known carriers should take care to have an adequate dietary intake of vitamin B12 and malabsorption syndromes like those occurring in familial pernicious anaemia or after gastric surgery should be excluded."
Allergies
Vitamin B12 supplements in theory should be avoided in people sensitive or allergicAllergy
An Allergy is a hypersensitivity disorder of the immune system. Allergic reactions occur when a person's immune system reacts to normally harmless substances in the environment. A substance that causes a reaction is called an allergen. These reactions are acquired, predictable, and rapid...
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.
Interactions
- Alcohol (ethanolEthanolEthanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
): Excessive alcohol intake lasting longer than two weeks can decrease vitamin B12 absorption from the gastrointestinal tract.
- Aminosalicylic acidAminosalicylic acid4-aminosalicylic acid, commonly known as PAS, is an antibiotic used to treat tuberculosis. This organic compound has been use since the 1940s for the treatment of inflammatory bowel diseases , where it has shown greater potency in ulcerative colitis and Crohn's disease. It is thought to act via...
(para-aminosalicylic acid, PAS, Paser): Aminosalicylic acid can reduce oral vitamin B12 absorption, possibly by as much as 55%, as part of a general malabsorption syndrome. Megaloblastic changes, and occasional cases of symptomatic anemia have occurred, usually after doses of 8 to 12 g/day for several months. Vitamin B12 levels should be monitored in people taking aminosalicylic acid for more than one month.
- Antibiotics: An increased bacterial load can bind significant amounts of vitamin B12 in the gut, preventing its absorption. In people with bacterial overgrowth of the small bowel, antibiotics such as metronidazoleMetronidazoleMetronidazole is a nitroimidazole antibiotic medication used particularly for anaerobic bacteria and protozoa. Metronidazole is an antibiotic, amebicide, and antiprotozoal....
(Flagyl) can actually improve vitamin B12 status. The effects of most antibiotics on gastrointestinal bacteriaBacteriaBacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
are unlikely to have clinically significant effects on vitamin B12 levels. - Hormonal contraceptionHormonal contraceptionHormonal contraception refers to birth control methods that act on the endocrine system. Almost all methods are composed of steroid hormones, although in India one selective estrogen receptor modulator is marketed as a contraceptive. The original hormonal method—the combined oral contraceptive...
: The data regarding the effects of oral contraceptives on vitamin B12serum levels are conflicting. Some studies have found reduced serum levels in oral contraceptive users, but others have found no effect despite use of oral contraceptives for up to 6 months. When oral contraceptive use is stopped, normalization of vitamin B12 levels usually occurs. Lower vitamin B12serum levels seen with oral contraceptives probably are not clinically significant.
- ChloramphenicolChloramphenicolChloramphenicol is a bacteriostatic antimicrobial that became available in 1949. It is considered a prototypical broad-spectrum antibiotic, alongside the tetracyclines, and as it is both cheap and easy to manufacture it is frequently found as a drug of choice in the third world.Chloramphenicol is...
(Chloromycetin): Limited case reports suggest that chloramphenicol can delay or interrupt the reticulocyteReticulocyteReticulocytes are immature red blood cells, typically composing about 1% of the red cells in the human body.Reticulocytes develop and mature in the red bone marrow and then circulate for about a day in the blood stream before developing into mature red blood cells. Like mature red blood cells,...
response to supplemental vitamin B12 in some patients. Blood counts should be monitored closely if this combination cannot be avoided. - Cobalt irradiation: Cobalt irradiation of the small bowel can decrease gastrointestinal (GI) absorption of vitamin B12.
- ColchicineColchicineColchicine is a medication used for gout. It is a toxic natural product and secondary metabolite, originally extracted from plants of the genus Colchicum...
: Colchicine in doses of 1.9 to 3.9 mg/day can disrupt normal intestinal mucosal function, leading to malabsorptionMalabsorptionMalabsorption is a state arising from abnormality in absorption of food nutrients across the gastrointestinal tract.Impairment can be of single or multiple nutrients depending on the abnormality...
of several nutrientNutrientA nutrient is a chemical that an organism needs to live and grow or a substance used in an organism's metabolism which must be taken in from its environment. They are used to build and repair tissues, regulate body processes and are converted to and used as energy...
s, including vitamin B12. Lower doses do not seem to have a significant effect on vitamin B12 absorption after 3 years of colchicine therapy. The significance of this interaction is unclear. Vitamin B12 levels should be monitored in people taking large doses of colchicine for prolonged periods.
- ColestipolColestipolColestipol is a bile acid sequestrant.It works in the gut trapping bile salts, and preventing them from being reabsorbed.This leads todecreased enterohepatic recirculation of bile salts,increased synthesis of new bile salts by the liver,...
(Colestid), cholestyramineCholestyramineCholestyramine or colestyramine is a bile acid sequestrant, which binds bile in the gastrointestinal tract to prevent its reabsorption. It is a strong ion exchange resin, which means that it can exchange its chloride anions with anionic bile acids in the gastrointestinal tract and bind them...
(Questran): These resinResinResin in the most specific use of the term is a hydrocarbon secretion of many plants, particularly coniferous trees. Resins are valued for their chemical properties and associated uses, such as the production of varnishes, adhesives, and food glazing agents; as an important source of raw materials...
s used for sequestering bile acidsBile acid sequestrantThe bile acid sequestrants are a group of medications used to bind certain components of bile in the gastrointestinal tract. They disrupt the enterohepatic circulation of bile acids by sequestering them and preventing their reabsorption from the gut. In general, they are classified as hypolipidemic...
to decrease cholesterolCholesterolCholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
, can decrease gastrointestinal (GI) absorption of vitamin B12. It is unlikely this interaction will deplete body stores of vitamin B12 unless there are other factors contributing to deficiency. In a group of children treated with cholestyramine for up to 2.5 years, there was not any change in serum vitamin B12 levels. Routine supplements are not necessary. - H2-receptor antagonists: include cimetidineCimetidineCimetidine INN is a histamine H2-receptor antagonist that inhibits the production of acid in the stomach. It is largely used in the treatment of heartburn and peptic ulcers. It is marketed by GlaxoSmithKline under the trade name Tagamet...
(Tagamet), famotidineFamotidineFamotidine is a histamine H2-receptor antagonist that inhibits stomach acid production, and it is commonly used in the treatment of peptic ulcer disease and gastroesophageal reflux disease . It is commonly marketed by Johnson & Johnson/Merck under the trade names Pepcidine and Pepcid and by...
(Pepcid), nizatidineNizatidineNizatidine is a histamine H2-receptor antagonist that inhibits stomach acid production, and commonly used in the treatment of peptic ulcer disease and gastroesophageal reflux disease...
(Axid), and ranitidineRanitidineRanitidine is a histamine H2-receptor antagonist that inhibits stomach acid production. It is commonly used in treatment of peptic ulcer disease and gastroesophageal reflux disease . Ranitidine is also used alongside fexofenadine and other antihistamines for the treatment of skin conditions...
(Zantac). Reduced secretion of gastric acidGastric acidGastric acid is a digestive fluid, formed in the stomach. It has a pH of 1 to 2 and is composed of hydrochloric acid , and large quantities of potassium chloride and sodium chloride...
and pepsinPepsinPepsin is an enzyme whose precursor form is released by the chief cells in the stomach and that degrades food proteins into peptides. It was discovered in 1836 by Theodor Schwann who also coined its name from the Greek word pepsis, meaning digestion...
produced by H2 blockers can reduce absorption of protein-bound (dietary) vitamin B12, but not of supplemental vitamin B12. Gastric acid is needed to release vitamin B12 from protein for absorption. Clinically significant vitamin B12 deficiency and megaloblastic anemia are unlikely, unless H2 blocker therapy is prolonged (2 years or more), or the person's diet is poor. It is also more likely if the person is rendered achlorhydricAchlorhydriaAchlorhydria or hypochlorhydria refers to states where the production of gastric acid in the stomach is absent or low, respectively. It is associated with various other medical problems.-Signs and symptoms:...
(with complete absence of gastric acid secretion), which occurs more frequently with proton pump inhibitors than H2 blockers. Vitamin B12 levels should be monitored in people taking high doses of H2 blockers for prolonged periods. - MetforminMetforminMetformin is an oral antidiabetic drug in the biguanide class. It is the first-line drug of choice for the treatment of type 2 diabetes, in particular, in overweight and obese people and those with normal kidney function. Its use in gestational diabetes has been limited by safety concerns...
(Glucophage): Metformin may reduce serum folic acid and vitamin B12 levels. These changes can lead to hyperhomocysteinemiaHyperhomocysteinemiaHyperhomocysteinemia or hyperhomocysteinaemia is a medical condition characterized by an abnormally large level of homocysteine in the blood....
, adding to the risk of cardiovascular disease in people with diabetes. There are also rare reports of megaloblastic anemia in people who have taken metformin for five years or more. Reduced serum levels of vitamin B12 occur in up to 30% of people taking metformin chronically. However, clinically significant deficiency is not likely to develop if dietary intake of vitamin B12 is adequate. Deficiency can be corrected with vitamin B12 supplements even if metformin is continued. The metformin-induced malabsorption of vitamin B12 is reversible by oral calcium supplementation. The general clinical significance of metformin upon B12 levels is as yet unknown. - NeomycinNeomycinNeomycin is an aminoglycoside antibiotic that is found in many topical medications such as creams, ointments, and eyedrops. The discovery of Neomycin dates back to 1949. It was discovered in the lab of Selman Waksman, who was later awarded the Nobel Prize in Physiology and medicine in 1951...
: Absorption of vitamin B12 can be reduced by neomycin, but prolonged use of large doses is needed to induce pernicious anemia. Supplements are not usually needed with normal doses. - NicotineNicotineNicotine is an alkaloid found in the nightshade family of plants that constitutes approximately 0.6–3.0% of the dry weight of tobacco, with biosynthesis taking place in the roots and accumulation occurring in the leaves...
: Nicotine can reduce serum vitamin B12 levels. The need for vitamin B12 supplementation in smokers has not been adequately studied. - Nitrous oxideNitrous oxideNitrous oxide, commonly known as laughing gas or sweet air, is a chemical compound with the formula . It is an oxide of nitrogen. At room temperature, it is a colorless non-flammable gas, with a slightly sweet odor and taste. It is used in surgery and dentistry for its anesthetic and analgesic...
: Nitrous oxide inactivates the cobalamin form of vitamin B12 by oxidation. Symptoms of vitamin B12 deficiency, including sensory neuropathy, myelopathyMyelopathyMyelopathy refers to pathology of the spinal cord. When due to trauma, it is known as spinal cord injury. When inflammatory, it is known as myelitis. Disease that is vascular in nature is known as vascular myelopathy....
, and encephalopathyEncephalopathyEncephalopathy means disorder or disease of the brain. In modern usage, encephalopathy does not refer to a single disease, but rather to a syndrome of global brain dysfunction; this syndrome can be caused by many different illnesses.-Terminology:...
, can occur within days or weeks of exposure to nitrous oxide anesthesiaAnesthesiaAnesthesia, or anaesthesia , traditionally meant the condition of having sensation blocked or temporarily taken away...
in people with subclinical vitamin B12 deficiency. Symptoms are treated with high doses of vitamin B12, but recovery can be slow and incomplete. People with normal vitamin B12 levels have sufficient vitamin B12 stores to make the effects of nitrous oxide insignificant, unless exposure is repeated and prolonged (such as recreational use). Vitamin B12 levels should be checked in people with risk factors for vitamin B12 deficiency prior to using nitrous oxide anesthesia. Chronic nitrous oxide B12 poisoning (usually from use of nitrous oxide as a recreational drug), however, may result in B12 functional deficiency even with normal measured blood levels of B12. - PhenytoinPhenytoinPhenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels...
(Dilantin), phenobarbitalPhenobarbitalPhenobarbital or phenobarbitone is a barbiturate, first marketed as Luminal by Friedr. Bayer et comp. It is the most widely used anticonvulsant worldwide, and the oldest still commonly used. It also has sedative and hypnotic properties but, as with other barbiturates, has been superseded by the...
, primidonePrimidonePrimidone is an anticonvulsant of the pyrimidinedione class, the active metabolites of which, phenobarbital and phenylethylmalonamide , are also anticonvulsants...
(Mysoline): These anticonvulsantAnticonvulsantThe anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
s have been associated with reduced vitamin B12 absorption, and reduced serum and cerebrospinal fluidCerebrospinal fluidCerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...
levels in some patients. This may contribute to the megaloblastic anemia, primarily caused by folate deficiency, associated with these drugs. It is also suggested that reduced vitamin B12 levels may contribute to the neuropsychiatric side effects of these drugs. Patients should be encouraged to maintain adequate dietary vitamin B12 intake. Folate and vitamin B12 status should be checked if symptoms of anemia develop. - Proton pump inhibitorProton pump inhibitorProton-pump inhibitors are a group of drugs whose main action is a pronounced and long-lasting reduction of gastric acid production. They are the most potent inhibitors of acid secretion available today. The group followed and has largely superseded another group of pharmaceuticals with similar...
s (PPIs): The PPIs include omeprazoleOmeprazoleOmeprazole is a proton pump inhibitor used in the treatment of dyspepsia, peptic ulcer disease , gastroesophageal reflux disease , laryngopharyngeal reflux and Zollinger–Ellison syndrome...
(Prilosec, Losec), lansoprazoleLansoprazoleLansoprazole is a proton-pump inhibitor which prevents the stomach from producing gastric acid. It is manufactured by a number of companies worldwide under several brand names . It was first approved by the U.S...
(Prevacid), rabeprazoleRabeprazoleRabeprazole is an antiulcer drug in the class of proton pump inhibitors. It was developed by Eisai Co. and is marketed by Janssen-Cilag as rabeprazole sodium under the brand names AcipHex in the US and Pariet in Britain, Italy, Greece, Australia, Brazil, Canada, Japan, and Russia. It is sold as...
(Aciphex), pantoprazolePantoprazolePantoprazole is a proton pump inhibitor drug that inhibits gastric acid secretion.-Use:...
(Protonix, Pantoloc), and esomeprazoleEsomeprazoleEsomeprazole is a proton pump inhibitor developed and marketed by AstraZeneca which is used in the treatment of dyspepsia, peptic ulcer disease , gastroesophageal reflux disease and Zollinger-Ellison syndrome...
(Nexium). The reduced secretion of gastric acid and pepsinPepsinPepsin is an enzyme whose precursor form is released by the chief cells in the stomach and that degrades food proteins into peptides. It was discovered in 1836 by Theodor Schwann who also coined its name from the Greek word pepsis, meaning digestion...
produced by PPIs can reduce absorption of protein-bound (dietary) vitamin B12, but not supplemental vitamin B12. Gastric acid is needed to release vitamin B12 from protein for absorption. Reduced vitamin B12 levels may be more common with PPIs than with H2-blockers, because they are more likely to produce achlorhydria (complete absence of gastric acid secretion). However, clinically significant vitamin B12 deficiency is unlikely, unless PPI therapy is prolonged (2 years or more) or dietary vitamin intake is low. Vitamin B12 levels should be monitored in people taking high doses of PPIs for prolonged periods. - ZidovudineZidovudineZidovudine or azidothymidine is a nucleoside analog reverse-transcriptase inhibitor , a type of antiretroviral drug used for the treatment of HIV/AIDS. It is an analog of thymidine....
(AZT, Combivir, Retrovir): Reduced serum vitamin B12 levels may occur when zidovudine therapy is started. This adds to other factors that cause low vitamin B12 levels in people with HIVHIVHuman immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
, and might contribute to the hematological toxicity associated with zidovudine. However, the data suggest vitamin B12 supplements are not helpful for people taking zidovudine. - Folic acidFolic acidFolic acid and folate , as well as pteroyl-L-glutamic acid, pteroyl-L-glutamate, and pteroylmonoglutamic acid are forms of the water-soluble vitamin B9...
: Folic acid, particularly in large doses, can mask vitamin B12 deficiency by completely correcting hematological abnormalities. In vitamin B12 deficiency, folic acid can produce complete resolution of the characteristic megaloblastic anemiaMegaloblastic anemiaMegaloblastic anemia is an anemia that results from inhibition of DNA synthesis in red blood cell production. When DNA synthesis is impaired, the cell cycle cannot progress from the G2 growth stage to the mitosis stage...
, while allowing potentially irreversible neurological damage (from continued inactivity of methylmalonyl mutase) to progress. Thus, vitamin B12 status should be determined before folic acid is given as monotherapy. - PotassiumPotassiumPotassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...
: Potassium supplements can reduce absorption of vitamin B12 in some people. This effect has been reported with potassium chloride and, to a lesser extent, with potassium citrate. Potassium might contribute to vitamin B12 deficiency in some people with other risk factors, but routine supplements are not necessary.
Structure
Vitamin B12 is a collection of cobaltCobalt
Cobalt is a chemical element with symbol Co and atomic number 27. It is found naturally only in chemically combined form. The free element, produced by reductive smelting, is a hard, lustrous, silver-gray metal....
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. The various forms (vitamer
Vitamer
A vitamer of a particular vitamin is any of a number of chemical substances, each of which shows vitamin activity. Very commonly each "vitamin" is not a single chemical, but rather multiple chemical substances called vitamers, each of which is defined by its different biological activity.For...
s) of B12 are all deeply red colored, due to the color of the cobalt-corrin complex.
Cyanocobalamin
Cyanocobalamin
Cyanocobalamin is an especially common vitamer of the vitamin B12 family. It is the most famous vitamer of the family, because it is, in chemical terms, the most air-stable...
is one such "vitamer
Vitamer
A vitamer of a particular vitamin is any of a number of chemical substances, each of which shows vitamin activity. Very commonly each "vitamin" is not a single chemical, but rather multiple chemical substances called vitamers, each of which is defined by its different biological activity.For...
" in this B complex
B vitamins
B vitamins are a group of water-soluble vitamins that play important roles in cell metabolism. The B vitamins were once thought to be a single vitamin, referred to as vitamin B . Later research showed that they are chemically distinct vitamins that often coexist in the same foods...
, 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 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, in as much as a number of substances (vitamer
Vitamer
A vitamer of a particular vitamin is any of a number of chemical substances, each of which shows vitamin activity. Very commonly each "vitamin" is not a single chemical, but rather multiple chemical substances called vitamers, each of which is defined by its different biological activity.For...
s) 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).
Pure cyanocoblamin possesses the deep pink colour associated with most octahedral cobalt(II) complexes and the crystals are well formed and easily grown up to millimetre size.
Hydroxocobalamin
Hydroxocobalamin
Hydroxocobalamin is a natural form, or vitamer, of vitamin B12, a basic member of the cobalamin family of compounds. Hydroxocobalamin is the form of vitamin B12 produced by many bacteria which are used to produce the vitamin commercially. Like other forms of vitamin B12, hydroxocobalamin has an...
is another form of B12 commonly encountered in pharmacology, but which is not normally present in the human body. Hydroxocobalamin is sometimes denoted B12a. This form of B12 is the form produced by bacteria, and is what is converted to cyanocobalmin in the commercial charcoal filtration step of production. Hydroxocobalamin has an avid affinity for cyanide
Cyanide
A cyanide is a chemical compound that contains the cyano group, -C≡N, which consists of a carbon atom triple-bonded to a nitrogen atom. Cyanides most commonly refer to salts of the anion CN−. Most cyanides are highly toxic....
ion and has been used as an antidote to cyanide poisoning. It is supplied typically in water solution for injection. Hydroxocobalamin is thought to be converted to the active enzymic forms of B12 more easily than cyanocobalamin, and since it is little more expensive than cyanocobalamin, and has 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.
B12 is the most chemically complex of all the vitamins. The structure of B12 is based on a corrin
Corrin
Corrin is an heterocyclic compound. It is the parent macrocycle related to substituted derivative that is found in vitamin B12. Its name reflects that it is the "core" of vitamin B12 .-Coordination chemistry:...
ring, which is similar to the porphyrin
Porphyrin
Porphyrins are a group of organic compounds, many naturally occurring. One of the best-known porphyrins is heme, the pigment in red blood cells; heme is a cofactor of the protein hemoglobin. Porphyrins are heterocyclic macrocycles composed of four modified pyrrole subunits interconnected at...
ring found in heme
Heme
A heme or haem is a prosthetic group that consists of an iron atom contained in the center of a large heterocyclic organic ring called a porphyrin. Not all porphyrins contain iron, but a substantial fraction of porphyrin-containing metalloproteins have heme as their prosthetic group; these are...
, chlorophyll
Chlorophyll
Chlorophyll is a green pigment found in almost all plants, algae, and cyanobacteria. Its name is derived from the Greek words χλωρος, chloros and φύλλον, phyllon . Chlorophyll is an extremely important biomolecule, critical in photosynthesis, which allows plants to obtain energy from light...
, and cytochrome
Cytochrome
Cytochromes are, in general, membrane-bound hemoproteins that contain heme groups and carry out electron transport.They are found either as monomeric proteins or as subunits of bigger enzymatic complexes that catalyze redox reactions....
. The central metal ion is cobalt
Cobalt
Cobalt is a chemical element with symbol Co and atomic number 27. It is found naturally only in chemically combined form. The free element, produced by reductive smelting, is a hard, lustrous, silver-gray metal....
. 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
Hydroxyl
A hydroxyl is a chemical group containing an oxygen atom covalently bonded with a hydrogen atom. In inorganic chemistry, the hydroxyl group is known as the hydroxide ion, and scientists and reference works generally use these different terms though they refer to the same chemical structure in...
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 hydrogenase
Hydrogenase
A hydrogenase is an enzyme that catalyses the reversible oxidation of molecular hydrogen . Hydrogenases play a vital role in anaerobic metabolism....
s and, by necessity, enzymes associated with cobalt utilization, involve metal-carbon bonds.
Synthesis and industrial production
Neither plants nor animals are independently capable of constructing vitamin B12. Only bacteriaBacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
have the enzymes required for its synthesis. The total synthesis of B12
Vitamin B12 total synthesis
Vitamin B12 total synthesis in chemistry describes the total synthesis of the complex biomolecule vitamin B12. A method first reported by the groups of Robert Burns Woodward and Albert Eschenmoser in 1973 is considered a classic in this research field....
was reported by Robert Burns Woodward
Robert Burns Woodward
Robert Burns Woodward was an American organic chemist, considered by many to be the preeminent organic chemist of the twentieth century...
and Albert Eschenmoser
Albert Eschenmoser
Albert Eschenmoser is a Swiss chemist working at the ETH Zurich and The Scripps Research Institute.His work together with Lavoslav Ružička on terpenes and the postulation of squalene cyclization to form lanosterol improved the insight into steroid biosynthesis.In the early 1960s, Eschenmoser began...
in 1972, and remains one of the classic feats of organic synthesis. Species from the following genera
Genus
In biology, a genus is a low-level taxonomic rank used in the biological classification of living and fossil organisms, which is an example of definition by genus and differentia...
are known to synthesize B12: Acetobacterium
Acetobacterium
Acetobacterium is a genus of gram-positive bacteria which belong to the Eubacteriaceae family. Usually they are homoacetogens, which means they predominantly produce acetic acid as a metabolic by-product. Not to be confused with acetic acid bacteria which are aerobic, gram-negative...
, Aerobacter, Agrobacterium
Agrobacterium
Agrobacterium is a genus of Gram-negative bacteria established by H. J. Conn that uses horizontal gene transfer to cause tumors in plants. Agrobacterium tumefaciens is the most commonly studied species in this genus...
, Alcaligenes
Alcaligenes
Alcaligenes is a genus of Gram-negative, aerobic, rod-shaped bacteria. The species are motile with one or more peritrichous flagella.Alcaligenes species have been used for the industrial production of non-standard amino acids; A. eutrophus also produces the biopolymer polyhydroxybutyrate .-External...
, Azotobacter
Azotobacter
Azotobacter is a genus of usually motile, oval or spherical bacteria that form thick-walled cysts and may produce large quantities of capsular slime. They are aerobic, free-living soil microbes which play an important role in the nitrogen cycle in nature, binding atmospheric nitrogen, which is...
, Bacillus
Bacillus
Bacillus is a genus of Gram-positive, rod-shaped bacteria and a member of the division Firmicutes. Bacillus species can be obligate aerobes or facultative anaerobes, and test positive for the enzyme catalase. Ubiquitous in nature, Bacillus includes both free-living and pathogenic species...
, Clostridium
Clostridium
Clostridium is a genus of Gram-positive bacteria, belonging to the Firmicutes. They are obligate anaerobes capable of producing endospores. Individual cells are rod-shaped, which gives them their name, from the Greek kloster or spindle...
, Corynebacterium
Corynebacterium
Corynebacterium is a genus of Gram-positive rod-shaped bacteria. They are widely distributed in nature and are mostly innocuous. Some are useful in industrial settings such as C. glutamicum. Others can cause human disease. C...
, Flavobacterium
Flavobacterium
Flavobacterium is a genus of Gram-negative, non-motile and motile, rod-shaped bacteria that consists of ten recognized species, as well as three newly proposed species . Flavobacteria are found in soil and fresh water in a variety of environments...
, Micromonospora
Micromonospora
Micromonospora is a genus of bacteria of the family Micromonosporaceae. They are gram-positive, spore-forming, generally aerobic, and form a branched mycelium; they occur as saprotrophic forms in soil and water...
, Mycobacterium
Mycobacterium
Mycobacterium is a genus of Actinobacteria, given its own family, the Mycobacteriaceae. The genus includes pathogens known to cause serious diseases in mammals, including tuberculosis and leprosy...
, Nocardia
Nocardia
Nocardia is a genus of weakly staining Gram-positive, catalase-positive, rod-shaped bacteria. It forms partially acid-fast beaded branching filaments . It has a total of 85 species. Some species are non-pathogenic while others are responsible for nocardiosis. Nocardia are found worldwide in soil...
,
Propionibacterium
Propionibacterium
Propionibacterium is a genus of bacteria named for their unique metabolism: They are able to synthesize propionic acid by using unusual transcarboxylase enzymes....
, Protaminobacter, Proteus
Proteus (bacterium)
Proteus is a genus of Gram-negative Proteobacteria.-Clinical significance:Three species—P. vulgaris, P. mirabilis, and P. penneri—are opportunistic human pathogens. Proteus includes pathogens responsible for many human urinary tract infections. P. mirabilis causes wound and urinary...
,
Pseudomonas
Pseudomonas
Pseudomonas is a genus of gammaproteobacteria, belonging to the family Pseudomonadaceae containing 191 validly described species.Recently, 16S rRNA sequence analysis has redefined the taxonomy of many bacterial species. As a result, the genus Pseudomonas includes strains formerly classified in the...
, Rhizobium
Rhizobium
Rhizobium is a genus of Gram-negative soil bacteria that fix nitrogen. Rhizobium forms an endosymbiotic nitrogen fixing association with roots of legumes and Parasponia....
, Salmonella
Salmonella
Salmonella is a genus of rod-shaped, Gram-negative, non-spore-forming, predominantly motile enterobacteria with diameters around 0.7 to 1.5 µm, lengths from 2 to 5 µm, and flagella which grade in all directions . They are chemoorganotrophs, obtaining their energy from oxidation and reduction...
, Serratia
Serratia
Serratia is a genus of Gram-negative, facultatively anaerobic, rod-shaped bacteria of the Enterobacteriaceae family. The most common species in the genus, S. marcescens, is normally the only pathogen and usually causes nosocomial infections. However, rare strains of S. plymuthica, S. liquefaciens,...
, Streptomyces
Streptomyces
Streptomyces is the largest genus of Actinobacteria and the type genus of the family Streptomycetaceae. Over 500 species of Streptomyces bacteria have been described. As with the other Actinobacteria, streptomycetes are gram-positive, and have genomes with high guanine and cytosine content...
, Streptococcus
Streptococcus
Streptococcus is a genus of spherical Gram-positive bacteria belonging to the phylum Firmicutes and the lactic acid bacteria group. Cellular division occurs along a single axis in these bacteria, and thus they grow in chains or pairs, hence the name — from Greek στρεπτος streptos, meaning...
and Xanthomonas
Xanthomonas
Xanthomonas is a genus of Proteobacteria, many of which cause plant diseases. Most varieties of Xanthomonas are available from the National Collection of Plant Pathogenic Bacteria in the United Kingdom and other international culture collections such as ICMP in New Zealand, CFBP in France, and...
.
Industrial production of B12 is through fermentation
Fermentation (biochemistry)
Fermentation is the process of extracting energy from the oxidation of organic compounds, such as carbohydrates, using an endogenous electron acceptor, which is usually an organic compound. In contrast, respiration is where electrons are donated to an exogenous electron acceptor, such as oxygen,...
of selected microorganisms. Streptomyces griseus
Streptomyces griseus
Streptomyces griseus is a member bacterial species of the genus Streptomyces and are commonly found in soil. A few strains have been also reported from deep sea sediments. These are Gram positive bacterium with high GC content. Along with most other streptomycetes S...
, a bacterium once thought to be a yeast, was the commercial source of vitamin B12 for many years. The species Pseudomonas denitrificans
Pseudomonas denitrificans
Pseudomonas denitrificans is a Gram-negative facultative anaerobic bacterium that performs denitrification. It was first isolated from garden soil in Vienna, Austria. It synthesizes vitamin B12. Based on 16S rRNA analysis, P. denitrificans has been placed in the P. pertucinogena group....
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
Rhône-Poulenc
-History of the company:The Company was founded in 1928 through the merger of Société des Usines Chimiques du Rhône from Lyon and Établissements Poulenc Frères from Paris founded by Étienne Poulenc, a 19th century Parisian apothecary and brought to prominence by his second and third sons Emile...
of France
France
The French Republic , The French Republic , The French Republic , (commonly known as France , is a unitary semi-presidential republic in Western Europe with several overseas territories and islands located on other continents and in the Indian, Pacific, and Atlantic oceans. Metropolitan France...
, which has merged into Sanofi-Aventis
Sanofi-Aventis
Sanofi S.A. is a multinational pharmaceutical company headquartered in Paris, France, the world's fourth-largest by prescription sales. Sanofi engages in the research and development, manufacturing and marketing of pharmaceutical products for sale principally in the prescription market, but the...
, used genetically engineered versions of one or both of these species. Since a number of species of Propionibacterium
Propionibacterium
Propionibacterium is a genus of bacteria named for their unique metabolism: They are able to synthesize propionic acid by using unusual transcarboxylase enzymes....
produce no exotoxin
Exotoxin
An exotoxin is a toxin excreted by a microorganism, like bacteria, fungi, algae, and protozoa. An exotoxin can cause damage to the host by destroying cells or disrupting normal cellular metabolism. They are highly potent and can cause major damage to the host...
s or endotoxin
Endotoxin
Endotoxins are toxins associated with some Gram-negative bacteria. An "endotoxin" is a toxin that is a structural molecule of the bacteria that is recognized by the immune system.-Gram negative:...
s and are generally regarded as safe (have been granted GRAS
Gras
Gras is a commune in the Ardèche department in southern France.-Population:-References:*...
status) by the Food and Drug Adminstration of the United States, they are presently the FDA-preferred bacterial fermentation organisms for vitamin B12 production.
The total world production of vitamin B12, by four companies (the French Sanofi-Aventis and three Chinese companies) is said to have been 35 tonnes in 2008. Most of this production is used as an additive to animal feed.
Mechanism of action
Folic acid
Folic acid and folate , as well as pteroyl-L-glutamic acid, pteroyl-L-glutamate, and pteroylmonoglutamic acid are forms of the water-soluble vitamin B9...
(vitamin B9), since B12 is used to regenerate folate in the body. Most vitamin B12 deficiency symptoms are actually folate deficiency symptoms, since they include all the effects of pernicious anemia
Pernicious anemia
Pernicious anemia is one of many types of the larger family of megaloblastic anemias...
and megaloblastosis, which are due to poor synthesis of DNA when the body does not have a proper supply of folic acid
Folic acid
Folic acid and folate , as well as pteroyl-L-glutamic acid, pteroyl-L-glutamate, and pteroylmonoglutamic acid are forms of the water-soluble vitamin B9...
for the production of thymine
Thymine
Thymine is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The others are adenine, guanine, and cytosine. Thymine is also known as 5-methyluracil, a pyrimidine nucleobase. As the name suggests, thymine may be derived by methylation of uracil at...
. When sufficient folic acid is available, all known B12 related deficiency syndromes normalize, save those narrowly connected with the vitamin B12-dependent enzymes Methylmalonyl Coenzyme A mutase, and 5-methyltetrahydrofolate-homocysteine methyltransferase
5-methyltetrahydrofolate-homocysteine methyltransferase
Methionine synthase also known as MS, MeSe, MetH is an enzyme that in humans is encoded by the MTR gene . This enzyme is responsible for the regeneration of methionine from homocysteine...
(MTR), also known as methionine synthase; and the buildup of their respective substrates (methylmalonic acid
Methylmalonic acid
Methylmalonic acid is a dicarboxylic acid that is a C-methylated derivative of malonate.The coenzyme A linked form of methylmalonic acid, methylmalonyl-CoA, is converted into succinyl-CoA by methylmalonyl-CoA mutase, in a reaction that requires vitamin B12 as a cofactor...
, MMA) and homocysteine
Homocysteine
Homocysteine is a non-protein amino acid with the formula HSCH2CH2CHCO2H. It is a homologue of the amino acid cysteine, differing by an additional methylene group. It is biosynthesized from methionine by the removal of its terminal Cε methyl group...
.
Coenzyme B12's reactive C-Co bond participates in three main types of enzyme-catalyzed reactions.
- Isomerases. Rearrangements in which a hydrogen atom is directly transferred between two adjacent atoms with concomitant exchange of the second substituent, X, which may be a carbon atom with substituents, an oxygen atom of an alcohol, or an amine.
- Methyltransferases. Methyl (-CH3) group transfers between two molecules.
- Dehalogenases. 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-CoASuccinyl-CoASuccinyl-Coenzyme A, abbreviated as Succinyl-CoA or SucCoA, is a combination of succinic acid and coenzyme A.-Source:It is an important intermediate in the citric acid cycle, where it is synthesized from α-Ketoglutarate by α-ketoglutarate dehydrogenase through decarboxylation...
, an important step in the extraction of energy from proteins and fats (for more see MUT's reaction mechanism). This functionality is lost in vitamin B12 deficiencyVitamin B12 deficiencyVitamin B12 deficiency or hypocobalaminemia is a low blood level of vitamin B12, it can cause permanent damage to nervous tissue as a long term effect. Vitamin B12 was discovered from its relationship to the disease pernicious anemia, which is an autoimmune disease that destroys parietal cells in...
, and can be measured clinically as an increased methylmalonic acidMethylmalonic acidMethylmalonic acid is a dicarboxylic acid that is a C-methylated derivative of malonate.The coenzyme A linked form of methylmalonic acid, methylmalonyl-CoA, is converted into succinyl-CoA by methylmalonyl-CoA mutase, in a reaction that requires vitamin B12 as a cofactor...
(MMA) level. Unfortunately, an elevated MMA, though sensitive to B12 deficiency, is probably overly sensitive, and not all who have it actually have B12 deficiency. For example, MMA is elevated in 90–98% of patients with B12 deficiency; however 20–25% of patients over the age of 70 have elevated levels of MMA, yet 25–33% of them do not 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 cannot be affected by folate supplementation, which is necessary for myelinMyelinMyelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
synthesis (see mechanism below) and certain other functions of the central nervous system. Other functions of B12 related to DNA synthesis related to MTR dysfunction (see below) can often be corrected with supplementation with the vitamin folic acidFolic acidFolic acid and folate , as well as pteroyl-L-glutamic acid, pteroyl-L-glutamate, and pteroylmonoglutamic acid are forms of the water-soluble vitamin B9...
, but not the elevated levels of homocysteine, which is normally converted to methionine by MTR. - MTR5-methyltetrahydrofolate-homocysteine methyltransferaseMethionine synthase also known as MS, MeSe, MetH is an enzyme that in humans is encoded by the MTR gene . This enzyme is responsible for the regeneration of methionine from homocysteine...
, also known as methionine synthase, is a methyltransferase enzyme, which uses the MeB12 and reaction type 2 to catalyze the conversion of the amino acidAmino acidAmino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
homocysteineHomocysteineHomocysteine is a non-protein amino acid with the formula HSCH2CH2CHCO2H. It is a homologue of the amino acid cysteine, differing by an additional methylene group. It is biosynthesized from methionine by the removal of its terminal Cε methyl group...
(Hcy) back into methionineMethionineMethionine is an α-amino acid with the chemical formula HO2CCHCH2CH2SCH3. This essential amino acid is classified as nonpolar. This amino-acid is coded by the codon AUG, also known as the initiation codon, since it indicates mRNA's coding region where translation into protein...
(Met) (for more see MTR's reaction mechanism). This functionality is lost in vitamin B12 deficiencyVitamin B12 deficiencyVitamin B12 deficiency or hypocobalaminemia is a low blood level of vitamin B12, it can cause permanent damage to nervous tissue as a long term effect. Vitamin B12 was discovered from its relationship to the disease pernicious anemia, which is an autoimmune disease that destroys parietal cells in...
, and can be measured clinically as an increased homocysteineHomocysteineHomocysteine is a non-protein amino acid with the formula HSCH2CH2CHCO2H. It is a homologue of the amino acid cysteine, differing by an additional methylene group. It is biosynthesized from methionine by the removal of its terminal Cε methyl group...
level in vitro. Increased homocysteine can also be caused by a folic acidFolic acidFolic acid and folate , as well as pteroyl-L-glutamic acid, pteroyl-L-glutamate, and pteroylmonoglutamic acid are forms of the water-soluble vitamin B9...
deficiency, since B12 helps to regenerate the tetrahydrofolate (THF) active form of folic acid. Without B12, folate is trapped as 5-methyl-folate, from which THF cannot be recovered unless a MTR process reacts the 5-methyl-folate with homocysteine to produce methionine and THF, thus decreasing the need for fresh sources of THF from the diet. THF may be produced in the conversion of homocysteine to methionine, or may be obtained in the diet. It is converted by a non-B12-dependent process to 5,10-methylene-THF, which is involved in the synthesis of thymineThymineThymine is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The others are adenine, guanine, and cytosine. Thymine is also known as 5-methyluracil, a pyrimidine nucleobase. As the name suggests, thymine may be derived by methylation of uracil at...
. Reduced availability of 5,10-methylene-THF results in problems with DNA synthesis, and ultimately in ineffective production cells with rapid turnover, in particular blood cells, and also intestinal wall cells which are responsible for absorption. The failure of blood cell production results in the once-dreaded and fatal disease, pernicious anemiaPernicious anemiaPernicious anemia is one of many types of the larger family of megaloblastic anemias...
. All of the DNA synthetic effects, including the megaloblastic anemiaMegaloblastic anemiaMegaloblastic anemia is an anemia that results from inhibition of DNA synthesis in red blood cell production. When DNA synthesis is impaired, the cell cycle cannot progress from the G2 growth stage to the mitosis stage...
of pernicious anemiaPernicious anemiaPernicious anemia is one of many types of the larger family of megaloblastic anemias...
, resolve if sufficient folate is present (since levels of 5,10-methylene-THF still remain adequate with enough dietary folate). Thus the best-known "function" of B12 (that which is involved with DNA synthesis, cell-division, and anemia) is actually a facultative function which is mediated by B12-conservation of an 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 methyl transferase.
Enzyme function
If folate is present in quantity, then of the two absolutely vitamin B12-dependent enzyme-family reactions in humans, the MUTMethylmalonyl-CoA mutase
Methylmalonyl Coenzyme A mutase, also known as MCM is an enzyme that catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA and it is involved in key metabolic pathways...
-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
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
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 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.
Vitamin B12-dependent MTR
5-methyltetrahydrofolate-homocysteine methyltransferase
Methionine synthase also known as MS, MeSe, MetH is an enzyme that in humans is encoded by the MTR gene . This enzyme is responsible for the regeneration of methionine from homocysteine...
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.
Absorption and distribution
The human physiology of vitamin B12 is complex, and therefore is prone to mishaps leading to vitamin B12 deficiencyVitamin B12 deficiency
Vitamin B12 deficiency or hypocobalaminemia is a low blood level of vitamin B12, it can cause permanent damage to nervous tissue as a long term effect. Vitamin B12 was discovered from its relationship to the disease pernicious anemia, which is an autoimmune disease that destroys parietal cells in...
. 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
Gastric acid
Gastric acid is a digestive fluid, formed in the stomach. It has a pH of 1 to 2 and is composed of hydrochloric acid , and large quantities of potassium chloride and sodium chloride...
releases the vitamin from food particles; therefore antacid
Antacid
An antacid is a substance which neutralizes stomach acidity.-Mechanism of action:Antacids perform a neutralization reaction, increasing the pH to reduce acidity in the stomach. When gastric hydrochloric acid reaches the nerves in the gastrointestinal mucosa, they signal pain to the central nervous...
and acid-blocking medications (especially proton-pump inhibitors) may inhibit absorption of B12. In addition some elderly people produce less stomach acid as they age thereby increasing their probability of B12 deficiencies.
B12 taken in a low-solubility, non-chewable supplement pill form may bypass the mouth and stomach and not mix with gastric acids, but these are not necessary for the absorption of free B12 not bound to protein.
R-proteins (such as haptocorrin
Haptocorrin
Haptocorrin also known as transcobalamin-1 is a protein that in humans is encoded by the TCN1 gene. The essential function of haptocorrin is protection of the acid-sensitive vitamin B12 while it moves through the stomach.- Function :...
s and cobalaphilin) are B12 binding proteins that are produced in the salivary glands. They must wait until B12 has been freed from proteins in food by pepsin
Pepsin
Pepsin is an enzyme whose precursor form is released by the chief cells in the stomach and that degrades food proteins into peptides. It was discovered in 1836 by Theodor Schwann who also coined its name from the Greek word pepsis, meaning digestion...
in the stomach. B12 then binds to the R-Proteins to avoid degradation of it in the acidic environment of the stomach.
This pattern of secretion of a binding protein secreted in a previous digestive step, is repeated once more before absorption. The next binding protein is intrinsic factor (IF), a protein synthesized by gastric parietal cell
Parietal cell
Parietal cells, or oxyntic cells, are the stomach epithelium cells that secrete gastric acid and intrinsic factor.Acetylcholine and gastrin . The histamine receptors act by increasing intracellular cAMP, whereas the muscarinic and gastrin receptors increase intracellular Ca2+ levels...
s that is secreted in response to histamine
Histamine
Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by...
, gastrin
Gastrin
In humans, gastrin is a peptide hormone that stimulates secretion of gastric acid by the parietal cells of the stomach and aids in gastric motility. It is released by G cells in the antrum of the stomach, duodenum, and the pancreas...
and pentagastrin
Pentagastrin
Pentagastrin is a synthetic polypeptide that has effects like gastrin when given parenterally. It stimulates the secretion of gastric acid, pepsin, and intrinsic factor, and has been used as a diagnostic aid as the pentagastrin-stimulated calcitonin test.Pentagastrin binds to the cholecystokinin-B...
, as well as the presence of food.
In the duodenum
Duodenum
The duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms anterior intestine or proximal intestine may be used instead of duodenum...
, protease
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
s digest R-proteins and release B12, which then binds to IF, to form a complex (IF/B12). B12 must be attached to IF for it to be absorbed, as receptors on the enterocytes in the terminal ileum
Ileum
The ileum is the final section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms posterior intestine or distal intestine may be used instead of ileum.The ileum follows the duodenum...
of the small bowel only recognize the B12-IF complex; in addition, intrinsic factor protects the vitamin from catabolism
Catabolism
Catabolism is the set of metabolic pathways that break down molecules into smaller units and release energy. In catabolism, large molecules such as polysaccharides, lipids, nucleic acids and proteins are broken down into smaller units such as monosaccharides, fatty acids, nucleotides, and amino...
by intestinal bacteria.
Absorption of food vitamin B12 thus requires an intact and functioning stomach
Stomach
The stomach is a muscular, hollow, dilated part of the alimentary canal which functions as an important organ of the digestive tract in some animals, including vertebrates, echinoderms, insects , and molluscs. It is involved in the second phase of digestion, following mastication .The stomach is...
, exocrine pancreas
Exocrine pancreas
The exocrine pancreas has ducts that are arranged in clusters called acini . Pancreatic secretions are secreted into the lumen of the acinus, and then accumulate in intralobular ducts that drain to the main pancreatic duct, which drains directly into the duodenum.Control of the exocrine function of...
, intrinsic factor, and small bowel. Problems with any one of these organs makes a vitamin B12 deficiency
Vitamin B12 deficiency
Vitamin B12 deficiency or hypocobalaminemia is a low blood level of vitamin B12, it can cause permanent damage to nervous tissue as a long term effect. Vitamin B12 was discovered from its relationship to the disease pernicious anemia, which is an autoimmune disease that destroys parietal cells in...
possible. Individuals who lack intrinsic factor have a decreased ability to absorb B12. In pernicious anemia
Pernicious anemia
Pernicious anemia is one of many types of the larger family of megaloblastic anemias...
, there is a lack of IF due to autoimmune atrophic gastritis
Atrophic gastritis
Atrophic gastritis is a process of chronic inflammation of the stomach mucosa, leading to loss of gastric glandular cells and their eventual replacement by intestinal and fibrous tissues...
, 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
Enterocyte
Enterocytes, or intestinal absorptive cells, are simple columnar epithelial cells found in the small intestines and colon. A glycocalyx surface coat contains digestive enzymes. Microvilli on the apical surface increase surface area for the digestion and transport of molecules from the intestinal...
, 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
Megaloblastic anemia
Megaloblastic anemia is an anemia that results from inhibition of DNA synthesis in red blood cell production. When DNA synthesis is impaired, the cell cycle cannot progress from the G2 growth stage to the mitosis stage...
, 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
Endocytosis
Endocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...
. The transcobalamin-II is degraded within a lysosome
Lysosome
thumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s: [[nucleoli]] [[cell nucleus|nucleus]] [[ribosomes]] [[vesicle |vesicle]] rough [[endoplasmic reticulum]]...
, and free B12 is finally released into the cytoplasm, where it may be transformed into the proper coenzyme, by certain cellular enzymes (see above).
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; however, most of the B12 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.
History
B12 deficiency is the cause of pernicious anemiaPernicious anemia
Pernicious anemia is one of many types of the larger family of megaloblastic anemias...
, an anemic disease that was usually fatal and had unknown etiology when it was first described in medicine. The cure, and B12, were discovered by accident. George Whipple
George Whipple
George Hoyt Whipple was an American physician, pathologist, biomedical researcher, and medical school educator and administrator...
had been doing experiments in which he induced anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
in dogs by bleeding them, and then 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
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
seemed to most-rapidly cure the anemia of blood loss. Thus, he hypothesized that liver ingestion might treat pernicious anemia. He tried this and reported some signs of success in 1920.
After a series of careful clinical studies, George Richards Minot and William Murphy
William Murphy (scientist)
William Parry Murphy was an American physician who shared the Nobel Prize in Physiology or Medicine in 1934 with George Richards Minot and George Hoyt Whipple for their combined work in devising and treating macrocytic anemia .Murphy was born on February 6, 1892, at Stoughton, Wisconsin...
set out to partly isolate the substance in liver which cured anemia in dogs, and found that it was iron
Iron
Iron is a chemical element with the symbol Fe and atomic number 26. It is a metal in the first transition series. It is the most common element forming the planet Earth as a whole, forming much of Earth's outer and inner core. It is the fourth most common element in the Earth's crust...
. They also found that an entirely different liver substance cured pernicious anemia in humans, that had no effect on dogs under the conditions used. The specific factor treatment for pernicious anemia, found in liver juice, had been found by this coincidence. Minot and Murphy reported these experiments in 1926. This was the first real progress with this disease. Despite this discovery, for several years patients were still required to eat large amounts of raw liver or to drink considerable amounts 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
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine administered by the Nobel Foundation, is awarded once a year for outstanding discoveries in the field of life science and medicine. It is one of five Nobel Prizes established in 1895 by Swedish chemist Alfred Nobel, the inventor of dynamite, in his will...
.
These events in turn eventually led to discovery of the soluble vitamin, called vitamin B12, in the liver juice. The vitamin in liver extracts was not isolated until 1948 by the contributions of chemists Mary Shaw Shorb and Karl A. Folkers of the United States and Alexander R. Todd of Great Britain. In 1947, while working for the Poultry Science Department at the University of Maryland, Mary Shorb (in a collaborative project with Folkers and Merck) was provided with a $400 grant to develop the LLD assay. The LLD assay led to the purification and characterization of Vitamin B12 as it caused rapid isolation of the anti-pernicious anemia factor. For this discovery, in 1949 Mary Shorb and Karl Folkers received the Mead Johnson Award from the American Society of Nutritional Sciences.
The chemical structure
Analytical chemistry
Analytical chemistry is the study of the separation, identification, and quantification of the chemical components of natural and artificial materials. Qualitative analysis gives an indication of the identity of the chemical species in the sample and quantitative analysis determines the amount of...
of the molecule was determined by Dorothy Crowfoot Hodgkin
Dorothy Crowfoot Hodgkin
Dorothy Mary Hodgkin OM, FRS , née Crowfoot, was a British chemist, credited with the development of protein crystallography....
and her team in 1956, based on crystallographic
Crystallography
Crystallography is the experimental science of the arrangement of atoms in solids. The word "crystallography" derives from the Greek words crystallon = cold drop / frozen drop, with its meaning extending to all solids with some degree of transparency, and grapho = write.Before the development of...
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.
Foods
| Food | µg vitamin B12/100g |
|---|---|
| Panfried beef liver | 83.1 |
| Simmered turkey giblets | 33.2 |
| Braunschweiger pork liver sausage | 20.1 |
| Raw Pacific oysters | 16.0 |
| Cooked Alaska king crab | 11.5 |
| Raw clams | 11.3 |
| Simmered chicken giblets | 9.4 |
| Swiss cheese | 3.34 |
| Beef (uncooked sirloin) | 1.15 |
| Egg (raw, whole chicken's egg) | 0.89 |
| Whole cow's milk | 0.45 |
| Raw chicken breast (see Salmonellosis Salmonellosis Salmonellosis is an infection with Salmonella bacteria. Most people infected with Salmonella develop diarrhea, fever, vomiting, and abdominal cramps 12 to 72 hours after infection. In most cases, the illness lasts four to seven days, and most people recover without treatment... ) |
0.20 |
Ultimately, animals must obtain vitamin B12 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 rumen
Rumen
The rumen, also known as a paunch, forms the larger part of the reticulorumen, which is the first chamber in the alimentary canal of ruminant animals. It serves as the primary site for microbial fermentation of ingested feed...
s, or (if fermenting plant material in the hindgut
Hindgut
The hindgut is the posterior part of the alimentary canal. In mammals, it includes the distal third of the transverse colon and the splenic flexure, the descending colon, sigmoid colon and rectum.-Blood flow:...
) by reingestion of cecotrope fæces.
Vitamin B12 is found in foods that come from animals, including fish and shellfish
Shellfish
Shellfish is a culinary and fisheries term for exoskeleton-bearing aquatic invertebrates used as food, including various species of molluscs, crustaceans, and echinoderms. Although most kinds of shellfish are harvested from saltwater environments, some kinds are found only in freshwater...
, meat (especially liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
), poultry
Poultry
Poultry are domesticated birds kept by humans for the purpose of producing eggs, meat, and/or feathers. These most typically are members of the superorder Galloanserae , especially the order Galliformes and the family Anatidae , commonly known as "waterfowl"...
, eggs, milk, and milk products. Egg
Egg (food)
Eggs are laid by females of many different species, including birds, reptiles, amphibians, and fish, and have probably been eaten by mankind for millennia. Bird and reptile eggs consist of a protective eggshell, albumen , and vitellus , contained within various thin membranes...
s are often mentioned as a good B12 source, but they also contain a factor that blocks absorption. However, the binding capacity of heat treated egg yolks and egg whites is markedly diminished after heat treatment. Certain insects such as termites contain B12 produced by their gut bacteria, in a way analogous to ruminant animals. An NIH Fact Sheet lists a variety of food sources of vitamin B12.
While lacto-ovo vegetarians usually get enough B12 through consuming dairy product
Dairy product
Dairy products are generally defined as foods produced from cow's or domestic buffalo's milk. They are usually high-energy-yielding food products. A production plant for such processing is called a dairy or a dairy factory. Raw milk for processing comes mainly from cows, and, to a lesser extent,...
s, vegan
Veganism
Veganism is the practice of eliminating the use of animal products. Ethical vegans reject the commodity status of animals and the use of animal products for any purpose, while dietary vegans or strict vegetarians eliminate them from their diet only...
s will lack B12 unless they consume B12-containing dietary supplements or B12-fortified foods.
Examples of fortified foods
Food fortification
Food fortification or enrichment is the process of adding micronutrients to food. It can be purely a commercial choice to provide extra nutrients in a food, or sometimes it is a public health policy which aims to reduce numbers of people with dietary deficiencies in a population.Diets that lack...
include fortified breakfast cereals, fortified soy
Soybean
The soybean or soya bean is a species of legume native to East Asia, widely grown for its edible bean which has numerous uses...
products, fortified energy bar
Energy bar
Energy bars are supplemental bars containing cereals and other high energy foods targeted at people that require quick energy but do not have time for a meal...
s, and fortified nutritional yeast
Nutritional yeast
Nutritional yeast is a deactivated yeast, usually Saccharomyces cerevisiae. The scientific work of Louis Pasteur made it possible to isolate yeast in pure culture form. Nutritional yeast is produced by culturing the yeast with a mixture of sugarcane and beet molasses for a period of 7 days and...
. According to the UK Vegan Society
Vegan Society
The Vegan Society is a registered charity and the oldest vegan society in the world, founded on November 1, 1944, in England by Donald Watson, Elsie "Sally" Shrigley, and 23 others....
, the present consensus is that any B12 present in plant foods is likely to be unavailable to humans because B12 analogues can compete with B12 and inhibit metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
.
Claimed sources of B12 that have been shown to be inadequate or unreliable through direct studies of vegans include laver
Laver (seaweed)
Laver is an edible algae often considered to be a seaweed that has a high mineral salt content, particularly iodine and iron. It is used for making laverbread, a traditional Welsh dish. Laver is common around the west coast of Britain and east coast of Ireland along the Irish Sea.It is smooth and...
(a seaweed
Seaweed
Seaweed is a loose, colloquial term encompassing macroscopic, multicellular, benthic marine algae. The term includes some members of the red, brown and green algae...
), barley
Barley
Barley is a major cereal grain, a member of the grass family. It serves as a major animal fodder, as a base malt for beer and certain distilled beverages, and as a component of various health foods...
grass, and human intestinal bacteria (human colonic bacteria produce B12, but it cannot be absorbed from the colon).
Supplements
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. It is a common ingredient in energy drinkEnergy drink
Energy drinks are beverages whose producers advertise that they "boost energy." These advertisements usually do not emphasize energy derived from the sugar and caffeine they contain but rather increased energy release due to a variety of stimulants and vitamins....
s and energy shot
Energy shot
Energy shots are a specialized kind of energy drink. Whereas most energy drinks are generally sold in cans or bottles, energy shots are usually sold in 50ml bottles. Energy shots normally contain nearly the same total amount of caffeine, vitamins or other functional ingredients as their larger...
s, usually at several times the minimum recommended daily allowance of B12.
Cyanocobalamin
Cyanocobalamin
Cyanocobalamin is an especially common vitamer of the vitamin B12 family. It is the most famous vitamer of the family, because it is, in chemical terms, the most air-stable...
is converted to its active forms, first hydroxocobalamin
Hydroxocobalamin
Hydroxocobalamin is a natural form, or vitamer, of vitamin B12, a basic member of the cobalamin family of compounds. Hydroxocobalamin is the form of vitamin B12 produced by many bacteria which are used to produce the vitamin commercially. Like other forms of vitamin B12, hydroxocobalamin has an...
and then methylcobalamin and adenosylcobalamin in the liver.
The sublingual route, in which B12 is presumably or supposedly absorbed more directly under the tongue, has not proven to be necessary or helpful, though there are a number of lozenges, pills, and even a lollipop designed for sublingual absorption. A 2003 study found no significant difference in absorption for serum levels from oral vs. sublingual delivery of 0.5 mg of cobalamin. Sublingual methods of replacement are effective only because of the typically high doses (0.5 mg), 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 gastro-intestinal tract absorption is impaired by gastric atrophy (pernicious anemia).
Injection and patches are sometimes used if digestive absorption is impaired, but there is evidence that this course of action may not be necessary with modern high potency oral supplements (such as 0.5 to 1 mg 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
Homocystinuria
Homocystinuria, also known as cystathionine beta synthase deficiency or CBS deficiency, is an inherited disorder of the metabolism of the amino acid methionine, often involving cystathionine beta synthase...
), treatment with intravenous, intramuscular hydroxocobalamin
Hydroxocobalamin
Hydroxocobalamin is a natural form, or vitamer, of vitamin B12, a basic member of the cobalamin family of compounds. Hydroxocobalamin is the form of vitamin B12 produced by many bacteria which are used to produce the vitamin commercially. Like other forms of vitamin B12, hydroxocobalamin has an...
or transdermal B12 is needed.
Non-cyano forms as supplements
Recently sublingual methylcobalamin has become available in 1 mg tablets. Such tablets have higher bioavailability than the older cyanocobalamin. No cyanideCyanide
A cyanide is a chemical compound that contains the cyano group, -C≡N, which consists of a carbon atom triple-bonded to a nitrogen atom. Cyanides most commonly refer to salts of the anion CN−. Most cyanides are highly toxic....
is released with methylcobolamin, although the amount of cyanide (2% of the weight, or 20 micrograms cyanide in a 1 mg cyanocobalamin tab) is far less than ingested in many natural foods. Although the safety of cyanocobalamin has not been seriously questioned, the safety of the other types is also well-established.
External links
- Vitamin B12 Fact Sheet from the U.S. National Institutes of HealthNational Institutes of HealthThe National Institutes of Health are an agency of the United States Department of Health and Human Services and are the primary agency of the United States government responsible for biomedical and health-related research. Its science and engineering counterpart is the National Science Foundation...
- Vitamin B12. Medline Plus (National Library of Medicine). Part of it was used for this article (US Government public domain), specially for drug and other interactions.
- Vitamin B12 deficiency article in American Family PhysicianAmerican Family PhysicianAmerican Family Physician is a semimonthly, peer-reviewed medical journal of the American Academy of Family Physicians. AFP’s chief objective is to provide high-quality continuing medical education for more than 190,000 family physicians and other primary care clinicians...
journal - Calculator for estimating the average daily Vitamin B12 intake
- Vitamin B12 at World's Healthiest Foods
See also
- CobamamideCobamamideCobamamide , which is also known as adenosylcobalamin and dibencozide, is, along with methylcobalamin , one of the active forms of vitamin B12...
- CyanocobalaminCyanocobalaminCyanocobalamin is an especially common vitamer of the vitamin B12 family. It is the most famous vitamer of the family, because it is, in chemical terms, the most air-stable...
- HydroxocobalaminHydroxocobalaminHydroxocobalamin is a natural form, or vitamer, of vitamin B12, a basic member of the cobalamin family of compounds. Hydroxocobalamin is the form of vitamin B12 produced by many bacteria which are used to produce the vitamin commercially. Like other forms of vitamin B12, hydroxocobalamin has an...
- Methylcobalamin