Created page with "シアノコバラミンは、B<sub>12</sub>の製造形態である。細菌発酵によってAdoB<sub>12</sub>とMeB<sub>12</sub>が生成され、亜硝酸ナトリウムと熱の存在下で青酸カリを加えることによってシアノコバラミンに変換される。シアノコバラミンが消費されると、生物学的に活性なAdoB<sub>12</sub>とMeB<sub>12</sub>に変換される。ビタミン{{chem|B|12}}の2つの生理活性型は、cytosol..."
Created page with "===貯蔵と排泄=== ビタミンB<sub>12</sub>の濃度がどれくらい速く変化するかは、食事から摂取される量、分泌される量、吸収される量のバランスに左右される。体内に貯蔵されているビタミンB<sub>12</sub>の総量は、成人で約2～5{{nbsp}}mgである。その約50％は肝臓に貯蔵されている。このうち約0.1％は腸への分泌物によって1日に失われるが、これはこれらの分..."
Cyanocobalamin is the most common form used in dietary supplements and [[food fortification]] because cyanide stabilizes the molecule against degradation. Methylcobalamin is also offered as a dietary supplement. There is no advantage to the use of adenosylcobalamin or methylcobalamin forms for the treatment of vitamin B<sub>12</sub> deficiency.
[[Hydroxocobalamin]] can be injected intramuscularly to treat vitamin B<sub>12</sub> deficiency. It can also be injected intravenously for the purpose of treating cyanide poisoning, as the hydroxyl group is displaced by cyanide, creating a non-toxic cyanocobalamin that is excreted in urine.
"Pseudovitamin B<sub>12</sub>" refers to compounds that are [[corrinoid]]s with a structure similar to the vitamin but without vitamin activity. Pseudovitamin B<sub>12</sub> is the majority corrinoid in [[Spirulina (dietary supplement)|spirulina]], an algal health food sometimes erroneously claimed as having this vitamin activity.
Vitamin B<sub>12</sub> deficiency can potentially cause severe and irreversible damage, especially to the brain and nervous system. Deficiency at levels only slightly lower than normal can cause a range of symptoms such as [[Fatigue (medical)|fatigue]], feeling weak, [[lightheadedness]], [[dizziness]], breathlessness, headaches, [[mouth ulcer]]s, upset stomach, decreased appetite, difficulty walking (staggering balance problems), muscle weakness, [[Depression (mood)|depression]], poor [[memory]], poor reflexes, confusion, and pale skin, [[Paresthesia|feeling abnormal sensations]], among others, especially in people over age 60. Vitamin B<sub>12</sub> deficiency can also cause symptoms of [[mania]] and [[psychosis]].
[[vitamin B12 deficiency/ja|ビタミンB12欠乏性]]貧血の主なタイプは[[pernicious anemia/ja|悪性貧血]]であり、[[List of medical triads and pentads/ja|症状の三徴候]]を特徴とする：
The main type of [[vitamin B12 deficiency]] anemia is [[pernicious anemia]], characterized by a [[List of medical triads and pentads|triad of symptoms]]:
# [[Anemia]] with bone marrow promegaloblastosis ([[megaloblastic anemia]]). This is due to the inhibition of [[DNA synthesis]] (specifically [[purines]] and [[thymidine]]).
# Gastrointestinal symptoms: alteration in bowel motility, such as mild [[diarrhea]] or [[constipation]], and loss of bladder or bowel control. These are thought to be due to defective DNA synthesis inhibiting replication in tissue sites with a high turnover of cells. This may also be due to the [[autoimmune]] attack on the [[parietal cell]]s of the stomach in pernicious anemia. There is an association with [[gastric antral vascular ectasia]] (which can be referred to as watermelon stomach), and pernicious anemia.
# Neurological symptoms: sensory or motor deficiencies (absent reflexes, diminished vibration or soft touch sensation) and [[subacute combined degeneration of spinal cord|subacute combined degeneration of the spinal cord]]. Deficiency symptoms in children include [[developmental delay]], [[developmental regression|regression]], [[irritability]], [[Abnormal involuntary movements|involuntary movements]] and [[hypotonia]].
Vitamin B<sub>12</sub> deficiency is most commonly caused by malabsorption, but can also result from low intake, immune gastritis, low presence of binding proteins, or use of certain medications. [[Vegan]]s—people who choose to not consume any animal-sourced foods—are at risk because plant-sourced foods do not contain the vitamin in sufficient amounts to prevent vitamin deficiency. [[Vegetarianism|Vegetarians]]—people who consume animal byproducts such as dairy products and eggs, but not the flesh of any animal—are also at risk. Vitamin B<sub>12</sub> deficiency has been observed in between 40% and 80% of the vegetarian population who do not also take a vitamin B<sub>12</sub> supplement or consume vitamin-fortified food. In Hong Kong and India, vitamin B<sub>12</sub> deficiency has been found in roughly 80% of the vegan population. As with vegetarians, vegans can avoid this by consuming a dietary supplement or eating B<sub>12</sub> fortified food such as cereal, plant-based milks, and [[nutritional yeast]] as a regular part of their diet. The elderly are at increased risk because they tend to produce less [[stomach acid]] as they age, a condition known as [[achlorhydria]], thereby increasing their probability of B<sub>12</sub> deficiency due to reduced absorption.
</div>
<div lang="en" dir="ltr" class="mw-content-ltr">
亜酸化窒素の過剰摂取や過剰使用は、ビタミンB12の活性な一価型を不活性な二価型に変換する。
Nitrous oxide overdose or overuse converts the active monovalent form of vitamin B12 to the inactive bivalent form.
The U.S. [[Dietary Reference Intake|Recommended Dietary Allowance (RDA)]] for pregnancy is {{value|2.6|u=µg/day}}, for lactation {{value|2.8|u=µg/day}}. Determination of these values was based on an RDA of {{value|2.4|u=µg/day}} for non-pregnant women, plus what will be transferred to the fetus during pregnancy and what will be delivered in breast milk. However, looking at the same scientific evidence, the [[European Food Safety Authority]] (EFSA) sets adequate intake (AI) at {{value|4.5|u=μg/day}} for pregnancy and {{value|5.0|u=μg/day}} for lactation. Low maternal vitamin B<sub>12</sub>, defined as serum concentration less than 148 pmol/L, increases the risk of miscarriage, preterm birth and newborn low birth weight.During pregnancy the [[placenta]] concentrates B<sub>12</sub>, so that newborn infants have a higher serum concentration than their mothers. As it is recently absorbed vitamin content that more effectively reaches the placenta, the vitamin consumed by the mother-to-be is more important than that contained in her liver tissue.
Women who consume little animal-sourced food, or who are vegetarian or vegan, are at higher risk of becoming vitamin depleted during pregnancy than those who consume more animal products. This depletion can lead to anemia, and also an increased risk that their breastfed infants become vitamin deficient. Vitamin B<sub>12</sub> is not one of the supplements recommended by the World Health Organization for healthy women who are pregnant, however vitamin B<sub>12</sub> is often suggested during pregnancy in a multivitamin along with folic acid especially for pregnant mothers who follow a vegetarian or vegan diet.
Low vitamin concentrations in human milk occur in families with low socioeconomic status or low consumption of animal products. Only a few countries, primarily in Africa, have mandatory food fortification programs for either wheat flour or maize flour; India has a voluntary fortification program. What the nursing mother consumes is more important than her liver tissue content, as it is recently absorbed vitamin that more effectively reaches breast milk. Breast milk B<sub>12</sub> decreases over months of nursing in both well-nourished and vitamin-deficient mothers. Exclusive or near-exclusive breastfeeding beyond six months is a strong indicator of low serum vitamin status in nursing infants. This is especially true when the vitamin status was poor during the pregnancy and if the early-introduced foods fed to the still breastfeeding infant are vegan.
Risk of deficiency persists if the post-weaning diet is low in animal products. Signs of low vitamin levels in infants and young children can include anemia, poor physical growth and neurodevelopmental delays. Children diagnosed with low serum B<sub>12</sub> can be treated with intramuscular injections, then transitioned to an oral dietary supplement.}
Various methods of gastric bypass or gastric restriction surgery are used to treat morbid obesity. Roux-en-Y gastric bypass surgery (RYGB) but not sleeve gastric bypass surgery or gastric banding, increases the risk of vitamin B<sub>12</sub> deficiency and requires preventive post-operative treatment with either injected or high-dose oral supplementation. For post-operative oral supplementation, {{value|1000|u=μg/day}} may be needed to prevent vitamin deficiency.
According to one review: "At present, no 'gold standard' test exists for the diagnosis of vitamin B<sub>12</sub> deficiency and as a consequence the diagnosis requires consideration of both the clinical state of the patient and the results of investigations." The vitamin deficiency is typically suspected when a routine complete blood count shows anemia with an elevated [[mean corpuscular volume]] (MCV). In addition, on the [[peripheral blood smear]], [[macrocyte]]s and hypersegmented [[polymorphonuclear leukocyte]]s may be seen. Diagnosis is supported based on vitamin B<sub>12</sub> blood levels below 150–180 [[Molar concentration#Units|pmol/L]] (200–250 [[Orders of magnitude (mass)#Picogram|pg/mL]]) in adults. However, serum values can be maintained while tissue B<sub>12</sub> stores are becoming depleted. Therefore, serum B<sub>12</sub> values above the cut-off point of deficiency do not necessarily confirm adequate B<sub>12</sub> status. For this reason, elevated serum [[homocysteine]] over 15 micromol/L and [[methylmalonic acid]] (MMA) over 0.271 micromol/L are considered better indicators of B<sub>12</sub> deficiency, rather than relying only on the concentration of B<sub>12</sub> in blood. However, elevated MMA is not conclusive, as it is seen in people with B<sub>12</sub> deficiency, but also in elderly people who have renal insufficiency, and elevated homocysteine is not conclusive, as it is also seen in people with folate deficiency. In addition, elevated methylmalonic acid levels may also be related to metabolic disorders such as [[methylmalonic acidemia]]. If nervous system damage is present and blood testing is inconclusive, a [[lumbar puncture]] may be carried out to measure [[cerebrospinal fluid]] B<sub>12</sub> levels.
Serum [[haptocorrin]] binds 80-90% of circulating B<sub>12</sub>, rendering it unavailable for cellular delivery by [[Transcobalamin|transcobalamin II]]. This is conjectured to be a circulating storage function. Several serious, even life-threatening diseases cause elevated serum HC, measured as abnormally high serum vitamin B<sub>12</sub>, while at the same time potentially manifesting as a symptomatic vitamin deficiency because of insufficent vitamin bound to transcobalamin II which transfers the vitamin to cells.
</div>
<div lang="en" dir="ltr" class="mw-content-ltr">
==医療用途==
==Medical uses==
{{Anchor|Medical uses}}
[[File:Hydroxocobalamin Injection.jpg|thumb|A vitamin B<sub>12</sub> solution (hydroxocobalamin) in a multi-dose bottle, with a single dose drawn up into a syringe for injection. Preparations are usually bright red.]]
Severe vitamin B<sub>12</sub> deficiency is initially corrected with daily intramuscular injections of {{value|1000|u=μg}} of the vitamin, followed by maintenance via monthly injections of the same amount or daily oral dosing of {{value|1000|u=μg}}. The daily dose is far in excess of the vitamin requirement because the normal transporter protein mediated absorption is absent, leaving only very inefficient intestinal passive absorption. Injection side effects include skin rash, itching, chills, fever, hot flushes, nausea and dizziness. Oral maintenance treatment avoids this problem and significantly reduces cost of treatment.
For [[cyanide]] poisoning, a large amount of hydroxocobalamin may be given [[intravenously]] and sometimes in combination with [[sodium thiosulfate]].
</div>
<div lang="en" dir="ltr" class="mw-content-ltr">
==食事に関する推奨事項==
==Dietary recommendations==
{{Anchor|Dietary recommendations}}
Some research shows that most people in the United States and the United Kingdom consume sufficient vitamin B<sub>12</sub>. However, other research suggests that the proportion of people with low or marginal levels of vitamin B<sub>12</sub> is up to 40% in the [[Western world]]. [[Grain]]-based foods can be [[food fortification|fortified]] by having the vitamin added to them. Vitamin B<sub>12</sub> supplements are available as single or multivitamin tablets. [[Pharmaceutical]] preparations of vitamin B<sub>12</sub> may be given by [[intramuscular injection]]. Since there are few non-animal sources of the vitamin, [[vegan]]s are advised to consume a [[dietary supplement]] or fortified foods for B<sub>12</sub> intake, or risk serious health consequences. Children in some regions of [[developing countries]] are at particular risk due to increased requirements during growth coupled with diets low in animal-sourced foods.
米国[[:en:National Academy of Medicine|医学アカデミー]]は1998年にビタミンB{{sub|12}}の推定平均必要量（EAR）と推奨食事許容量（RDA）を更新した。14歳以上の女性と男性のビタミンB{{sub|12}}のEARは2.0{{nbsp}}μg/日であり、RDAは{{value|2.4|u=μg/日}}である。RDAはEARより高いが、これは平均より必要量の多い人をカバーする量を特定するためである。妊娠中のRDAは2.6{{nbsp}}μg/dayである。授乳期のRDAは{{value|2.8|u=μg/day}}に等しい。12ヵ月までの乳児の場合、適切な摂取量（AI）は0.4～0.5{{nbsp}}μg/dayである（AIは、EARとRDAを決定するのに十分な情報がない場合に設定される）。1～13歳の子供の場合、RDAは年齢とともに0.9～1.8{{nbsp}}μg/dayと増加する。高齢者の10～30％は食品に含まれるビタミンB{{sub|12}}を効果的に吸収できない可能性があるため、50歳以上の高齢者は主にビタミンB{{sub|12}}を強化した食品やビタミンB{{sub|12}}を含むサプリメントを摂取することでRDAを満たすことが望ましい。安全性に関しては、十分なエビデンスがある場合には、ビタミンやミネラルについて[[tolerable upper intake level/ja|耐容上限摂取量]]（ULと呼ばれる）が設定されている。ビタミンB{{sub|12}}の場合、高用量摂取による有害作用に関するヒトでのデータがないため、ULは設定されていない。EAR、RDA、AI、ULを総称して[[dietary reference intake/ja|食事摂取基準量]]（DRI）と呼ぶ。
The US [[National Academy of Medicine]] updated estimated average requirements (EARs) and recommended dietary allowances (RDAs) for vitamin B{{sub|12}} in 1998. The EAR for vitamin B{{sub|12}} for women and men ages 14 and up is 2.0{{nbsp}}μg/day; the RDA is {{value|2.4|u=μg/day}}. RDA is higher than EAR so as to identify amounts that will cover people with higher than average requirements. RDA for pregnancy equals 2.6{{nbsp}}μg/day. RDA for lactation equals {{value|2.8|u=μg/day}}. For infants up to 12 months the adequate intake (AI) is 0.4–0.5{{nbsp}}μg/day. (AIs are established when there is insufficient information to determine EARs and RDAs.) For children ages 1–13 years the RDA increases with age from 0.9 to 1.8{{nbsp}}μg/day. Because 10 to 30 percent of older people may be unable to effectively absorb vitamin B{{sub|12}} naturally occurring in foods, it is advisable for those older than 50 years to meet their RDA mainly by consuming foods fortified with vitamin B{{sub|12}} or a supplement containing vitamin B{{sub|12}}. As for safety, [[tolerable upper intake level]]s (known as ULs) are set for vitamins and minerals when evidence is sufficient. In the case of vitamin B{{sub|12}} there is no UL, as there is no human data for adverse effects from high doses. Collectively the EARs, RDAs, AIs and ULs are referred to as [[dietary reference intake]]s (DRIs).
The [[European Food Safety Authority]] (EFSA) refers to the collective set of information as "dietary reference values", with population reference intake (PRI) instead of RDA, and average requirement instead of EAR. AI and UL are defined by EFSA the same as in the United States. For women and men over age 18 the adequate intake (AI) is set at 4.0{{nbsp}}μg/day. AI for pregnancy is 4.5 μg/day, for lactation 5.0{{nbsp}}μg/day. For children aged 1–14 years the AIs increase with age from 1.5 to 3.5{{nbsp}}μg/day. These AIs are higher than the U.S. RDAs. The EFSA also reviewed the safety question and reached the same conclusion as in the United States—that there was not sufficient evidence to set a UL for vitamin B{{sub|12}}.
</div>
<div lang="en" dir="ltr" class="mw-content-ltr">
国立健康・栄養研究所は、12歳以上の推奨摂取量を2.4{{nbsp}}μg/日と定めている。また、[[World Health Organization/ja|世界保健機関（WHO）]]もこのビタミンの成人推奨栄養摂取量として2.4{{nbsp}}μg/日を用いている。
The Japan National Institute of Health and Nutrition set the RDA for people ages 12 and older at 2.4{{nbsp}}μg/day. The [[World Health Organization]] also uses 2.4{{nbsp}}μg/day as the adult recommended nutrient intake for this vitamin.
For U.S. food and dietary supplement labeling purposes, the amount in a serving is expressed as a "percent of daily value" (%DV). For vitamin B{{sub|12}} labeling purposes, 100% of the daily value was 6.0{{nbsp}}μg, but on May 27, 2016, it was revised downward to 2.4{{nbsp}}μg. Compliance with the updated labeling regulations was required by 1 January 2020 for manufacturers with [[US$]]10 million or more in annual food sales, and by 1 January 2021 for manufacturers with lower volume food sales. A table of the old and new adult daily values is provided at [[Reference Daily Intake]].
</div>
<div lang="en" dir="ltr" class="mw-content-ltr">
==摂取源==
==Sources==
{{Anchor|Sources}}
===Bacteria and archaea===
===バクテリアと古細菌===
Vitamin B<sub>12</sub> is produced in nature by certain [[bacteria]], and [[archaea]]. It is synthesized by some bacteria in the [[gut microbiota]] in humans and other animals, but it has long been thought that humans cannot absorb this as it is made in the [[Large intestine|colon]], downstream from the [[small intestine]], where the absorption of most nutrients occurs. [[Ruminant]]s, such as cows and sheep, are foregut fermenters, meaning that plant food undergoes microbial fermentation in the [[rumen]] before entering the true stomach ([[abomasum]]), and thus they are absorbing vitamin B<sub>12</sub> produced by bacteria.
Other mammalian species (examples: [[rabbit]]s, [[pika]]s, [[beaver]], [[guinea pigs]]) consume high-fibre plants which pass through the gastrointestinal tract and undergo bacterial fermentation in the [[cecum]] and [[large intestine]]. In this [[hindgut fermentation]], the material from the cecum is expelled as "[[cecotrope]]s" and are re-ingested, a practice referred to as [[cecotrope|cecotrophy]]. Re-ingestion allows for absorption of nutrients made available by bacterial fermentation, and also of vitamins and other nutrients synthesized by the gut bacteria, including vitamin B<sub>12</sub>.
Non-ruminant, non-hindgut herbivores may have an enlarged forestomach and/or small intestine to provide a place for bacterial fermentation and B-vitamin production, including B<sub>12</sub>. For gut bacteria to produce vitamin B<sub>12</sub>, the animal must consume sufficient amounts of [[Bush sickness|cobalt]]. Soil that is deficient in cobalt may result in B<sub>12</sub> deficiency, and B<sub>12</sub> injections or cobalt supplementation may be required for livestock.
</div>
<div lang="en" dir="ltr" class="mw-content-ltr">
=== 動物由来の食品 ===
=== Animal-derived foods ===
動物は食事から摂取したビタミンB<sub>12</sub>を[[liver/ja|肝臓]]や[[muscle/ja|筋肉]]に蓄え、そのビタミンを[[egg as food/ja|卵]]や[[milk/ja|牛乳]]に取り込むものもある。したがって、肉、レバー、卵、牛乳は、人間を含む他の動物にとってのビタミン源である。昆虫は動物（他の昆虫や人間を含む）にとってB<sub>12</sub>の供給源である。ビタミンB<sub>12</sub>を多く含む動物由来の食品源としては、[[liver (food)/ja|レバー]]や、[[lamb and mutton/ja|羊肉]]、[[veal/ja|子牛肉]]、[[beef/ja|牛肉]]、[[turkey meat/ja|七面鳥]]などの[[organ meat/ja|内臓肉]]、また[[shellfish/ja|貝類]]や[[crab meat/ja|カニ肉]]などがある。
Animals store vitamin B<sub>12</sub> from their diets in their [[liver]]s and [[muscle]]s and some pass the vitamin into their [[Egg as food|eggs]] and [[milk]]. Meat, liver, eggs and milk are therefore sources of the vitamin for other animals, including humans. Insects are a source of B<sub>12</sub> for animals (including other insects and humans). Animal-derived food sources with a high concentration of vitamin B<sub>12</sub> include [[Liver (food)|liver]] and other [[organ meat]]s from [[Lamb and mutton|lamb]], [[veal]], [[beef]], and [[Turkey meat|turkey]]; also [[shellfish]] and [[crab meat]].
</div>
<div lang="en" dir="ltr" class="mw-content-ltr">
===植物と藻類===
===Plants and algae===
植物性食品のバクテリアによる発酵や藻類とバクテリアの共生関係によってビタミンB<sub>12</sub>が摂取できるという証拠がいくつかある。しかし、[[Academy of Nutrition and Dietetics/ja|栄養・食事療法学会]]は植物や藻類からの摂取は「信頼できない」と考えており、代わりに[[veganism/ja|ビーガン]]は強化食品やサプリメントに頼るべきだと述べている。
There is some evidence that bacterial fermentation of plant foods and symbiotic relationships between algae and bacteria can provide vitamin B<sub>12</sub>. However, the [[Academy of Nutrition and Dietetics]] considers plant and algae sources "unreliable", stating that [[Veganism|vegans]] should turn to fortified foods and supplements instead.
Natural plant and [[algae]] sources of vitamin B<sub>12</sub> include [[fermentation|fermented]] plant foods such as [[tempeh]] and seaweed-derived foods such as [[nori]] and [[laverbread]]. Methylcobalamin has been identified in ''[[Chlorella vulgaris]]''. Since only bacteria and some archea possess the genes and enzymes necessary to synthesize vitamin B<sub>12</sub>, plant and algae sources all obtain the vitamin secondarily from symbiosis with various species of bacteria, or in the case of fermented plant foods, from bacterial fermentation.
Foods for which vitamin B<sub>12</sub>-fortified versions are available include [[breakfast cereals]], plant-derived [[milk substitute]]s such as [[soy milk]] and [[oat milk]], [[energy bar]]s, and [[nutritional yeast]]. The fortification ingredient is cyanocobalamin. Microbial fermentation yields adenosylcobalamin, which is then converted to cyanocobalamin by addition of potassium cyanide or thiocyanate in the presence of sodium nitrite and heat.
As of 2019, nineteen countries require food fortification of wheat flour, maize flour or rice with vitamin B<sub>12</sub>. Most of these are in southeast Africa or Central America.
Vitamin B<sub>12</sub> is included in multivitamin pills; in some countries grain-based foods such as bread and pasta are fortified with B<sub>12</sub>. In the US, non-prescription products can be purchased providing up to 5,000{{nbsp}}µg each, and it is a common ingredient in [[energy drink]]s and [[energy shot]]s, usually at many times the recommended dietary allowance of B<sub>12</sub>. The vitamin can also be supplied on prescription and delivered via injection or other means.
[[Sublingual administration|Sublingual]] [[methylcobalamin]], which contains no [[cyanide]], is available in 5{{nbsp}}mg tablets. The metabolic fate and biological distribution of methylcobalamin are expected to be similar to that of other sources of vitamin B<sub>12</sub> in the diet. The amount of cyanide in cyanocobalamin is generally not a concern, even in the 1,000{{nbsp}}µg dose, since the amount of cyanide there (20{{nbsp}}µg in a 1,000{{nbsp}}µg cyanocobalamin tablet) is less than the daily consumption of cyanide from food, and therefore cyanocobalamin is not considered a health risk.
Injection of [[hydroxycobalamin]] is often used if digestive absorption is impaired, but this course of action may not be necessary with high-dose oral supplements (such as 0.5–1.0{{nbsp}}mg or more), because with large quantities of the vitamin taken orally, even the 1% to 5% of free crystalline B<sub>12</sub> that is absorbed along the entire intestine by passive diffusion may be sufficient to provide a necessary amount.
A person with cobalamin C disease (which results in combined [[methylmalonic aciduria]] and [[homocystinuria]]) may require treatment with intravenous or intramuscular hydroxocobalamin or transdermal B<sub>12</sub>, because oral cyanocobalamin is inadequate in the treatment of cobalamin C disease.
</div>
<div lang="en" dir="ltr" class="mw-content-ltr">
=== ビタミンB<sub>12</sub>の補給に使われるナノテクノロジー ===
=== Nanotechnologies used in vitamin B<sub>12</sub> supplementation ===
Conventional administration does not ensure specific distribution and controlled release of vitamin B<sub>12</sub>. Moreover, therapeutic protocols involving injection require health care people and commuting of patients to the hospital thus increasing the cost of the treatment and impairing the lifestyle of patients. Targeted delivery of vitamin B<sub>12</sub> is a major focus of modern prescriptions. For example, conveying the vitamin to the bone marrow and nerve cells would help myelin recovery. Currently, several nanocarriers strategies are being developed for improving vitamin B<sub>12</sub> delivery with the aim to simplify administration, reduce costs, improve pharmacokinetics, and ameliorate the quality of patients' lives.
Pseudovitamin-B<sub>12</sub> refers to B<sub>12</sub>-like analogues that are biologically inactive in humans. Most cyanobacteria, including ''[[Spirulina (dietary supplement)|Spirulina]]'', and some algae, such as ''[[Porphyra]] tenera'' (used to make a dried seaweed food called [[nori]] in Japan), have been found to contain mostly pseudovitamin-B<sub>12</sub> instead of biologically active B<sub>12</sub>. These pseudo-vitamin compounds can be found in some types of shellfish, in edible insects, and at times as metabolic breakdown products of cyanocobalamin added to dietary supplements and fortified foods.
Pseudovitamin-B<sub>12</sub> can show up as biologically active vitamin B<sub>12</sub> when a microbiological assay with ''Lactobacillus delbrueckii'' subsp. lactis is used, as the bacteria can utilize the pseudovitamin despite it being unavailable to humans. To get a reliable reading of B<sub>12</sub> content, more advanced techniques are available. One such technique involves pre-separation by [[silica gel]] and then assessment with B<sub>12</sub>-dependent ''E. coli'' bacteria.
A related concept is [[antivitamin]] B<sub>12</sub>, compounds (often synthetic B<sub>12</sub> analogues) that not only have no vitamin action, but also actively interfere with the activity of true vitamin B<sub>12</sub>. The design of these compounds mainly involve replacement of the metal ion with [[rhodium]], [[nickel]], or [[zinc]]; or the attachment of an inactive ligand such as 4-ethylphenyl. These compounds have the potential to be used for analyzing B<sub>12</sub> utilization pathways or even attacking B<sub>12</sub>-dependent pathogens.
</div>
<div lang="en" dir="ltr" class="mw-content-ltr">
== 薬物相互作用==
== Drug interactions ==
{{Anchor|Drug interactions}}
===H<sub>2</sub>-receptor antagonists and proton-pump inhibitors===
===H<sub>2</sub>受容体拮抗薬とプロトンポンプ阻害薬===
Gastric acid is needed to release vitamin B<sub>12</sub> from protein for absorption. Reduced secretion of [[gastric acid]] and [[pepsin]], from the use of [[H2 antagonist|H<sub>2</sub> blocker]] or [[proton-pump inhibitor]] (PPI) drugs, can reduce absorption of protein-bound (dietary) vitamin B<sub>12</sub>, although not of supplemental vitamin B<sub>12</sub>. H<sub>2</sub>-receptor antagonist examples include [[cimetidine]], [[famotidine]], [[nizatidine]], and [[ranitidine]]. PPIs examples include [[omeprazole]], [[lansoprazole]], [[rabeprazole]], [[pantoprazole]], and [[esomeprazole]]. Clinically significant vitamin B<sub>12</sub> deficiency and megaloblastic anemia are unlikely, unless these drug therapies are prolonged for two or more years, or if in addition the person's dietary intake is below recommended levels. Symptomatic vitamin deficiency is more likely if the person is rendered [[achlorhydria|achlorhydric]] (a complete absence of gastric acid secretion), which occurs more frequently with proton pump inhibitors than H<sub>2</sub> blockers.
Reduced serum levels of vitamin B<sub>12</sub> occur in up to 30% of people taking long-term [[anti-diabetic medication|anti-diabetic]] [[metformin]]. Deficiency does not develop if dietary intake of vitamin B<sub>12</sub> is adequate or prophylactic B<sub>12</sub> supplementation is given. If the deficiency is detected, metformin can be continued while the deficiency is corrected with B<sub>12</sub> supplements.
Certain medications can decrease the absorption of orally consumed vitamin B<sub>12</sub>, including [[colchicine]], extended-release [[potassium]] products, and antibiotics such as [[gentamicin]], [[neomycin]] and [[tobramycin]]. Anti-seizure medications [[phenobarbital]], [[pregabalin]], [[primidone]] and [[topiramate]] are associated with lower than normal serum vitamin concentration. However, serum levels were higher in people prescribed [[valproate]]. In addition, certain drugs may interfere with laboratory tests for the vitamin, such as [[amoxicillin]], [[erythromycin]], [[methotrexate]] and [[pyrimethamine]].
</div>
<div lang="en" dir="ltr" class="mw-content-ltr">
==化学==
==Chemistry==
{{Anchor|Chemistry}}
[[File:B12 methylcobalamin.jpg|thumb|200px|Methylcobalamin (shown) is a form of vitamin B<sub>12</sub>. Physically it resembles the other forms of vitamin B<sub>12</sub>, occurring as dark red crystals that freely form cherry-colored transparent solutions in water.]]
Vitamin B<sub>12</sub> is the most chemically complex of all the vitamins. The structure of B<sub>12</sub> is based on a [[corrin]] ring, which is similar to the [[porphyrin]] ring found in [[heme]]. The central metal ion is [[cobalt]]. As isolated as an air-stable solid and available commercially, cobalt in vitamin B<sub>12</sub> (cyanocobalamin and other vitamers) is present in its +3 oxidation state. Biochemically, the cobalt center can take part in both two-electron and one-electron reductive processes to access the "reduced" (B<sub>12r</sub>, +2 oxidation state) and "super-reduced" (B<sub>12s</sub>, +1 oxidation state) forms. The ability to shuttle between the +1, +2, and +3 oxidation states is responsible for the versatile chemistry of vitamin B<sub>12</sub>, allowing it to serve as a donor of deoxyadenosyl radical (radical alkyl source) and as a methyl cation equivalent (electrophilic alkyl source).
Four of the six coordination sites are provided by the corrin ring, and a fifth by a [[dimethylbenzimidazole]] group. The sixth coordination site, the [[reactive center]], is variable, being a [[Cyanide|cyano group]] (–CN), a [[hydroxyl]] group (–OH), a [[methyl]] group (–CH<sub>3</sub>) or a 5′-deoxy[[Adenosine|adenosyl]] group. Historically, the covalent carbon–cobalt bond is one of the 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. Animals have the ability to convert cyanocobalamin and hydroxocobalamin to the bioactive forms adenosylcobalamin and methylcobalamin by means of enzymatically replacing the cyano or hydroxyl groups.
[[File:Cobalamin-general-structure-color.png|thumb|The structures of the four most common vitamers of cobalamin, together with some synonyms. The structure of the 5'-deoxyadenosyl group, which forms the R group of adenosylcobalamin is also shown.|400px]]
</div>
<div lang="en" dir="ltr" class="mw-content-ltr">
=== 食品中のビタミンB<sub>12</sub>の分析方法===
=== Methods for the analysis of vitamin B<sub>12</sub> in food ===
Several methods have been used to determine the vitamin B<sub>12</sub> content in foods including microbiological assays, chemiluminescence assays, polarographic, spectrophotometric and high-performance liquid chromatography processes. The microbiological assay has been the most commonly used assay technique for foods, utilizing certain vitamin B<sub>12</sub>-requiring microorganisms, such as [[Lactobacillus delbrueckii subsp. lactis|''Lactobacillus delbrueckii'' subsp. ''lactis'']] ATCC7830. However, it is no longer the reference method due to the high measurement uncertainty of vitamin B<sub>12</sub>.
Furthermore, this assay requires overnight incubation and may give false results if any inactive vitamin B<sub>12</sub> analogues are present in the foods. Currently, radioisotope dilution assay (RIDA) with labelled vitamin B<sub>12</sub> and hog IF (pigs) have been used to determine vitamin B<sub>12</sub> content in food. Previous reports have suggested that the RIDA method is able to detect higher concentrations of vitamin B<sub>12</sub> in foods compared to the microbiological assay method.
Vitamin B<sub>12</sub> functions as a [[coenzyme]], meaning that its presence is required in some enzyme-catalyzed reactions. Listed here are the three classes of enzymes that sometimes require B<sub>12</sub> to function (in animals):
#: Rearrangements in which a hydrogen atom is directly transferred between two adjacent atoms with concomitant exchange of the second substituent, X, which may be a carbon atom with substituents, an oxygen atom of an alcohol, or an amine. These use the adoB<sub>12</sub> (adenosylcobalamin) form of the vitamin.
#: Some species of anaerobic bacteria synthesize B<sub>12</sub>-dependent dehalogenases, which have potential commercial applications for degrading chlorinated pollutants. The microorganisms may either be capable of ''de novo'' corrinoid biosynthesis or are dependent on exogenous vitamin B<sub>12</sub>.
In humans, two major coenzyme B<sub>12</sub>-dependent enzyme families corresponding to the first two reaction types, are known. These are typified by the following two enzymes:
[[File:Folate methionine cycle.svg|thumb|Simplified schematic diagram of the folate methionine cycle. Methionine synthase transfers the methyl group to the vitamin and then transfers the methyl group to homocysteine, converting that to methionine.|400px]]
[[Methylmalonyl-CoA mutase|Methylmalonyl coenzyme A mutase]] (MUT) is an isomerase enzyme which uses the AdoB<sub>12</sub> form and reaction type 1 to convert [[L-methylmalonyl-CoA]] to [[succinyl-CoA]], an important step in the catabolic breakdown of some [[amino acid]]s into succinyl-CoA, which then enters energy production via the [[citric acid cycle]]. This functionality is lost in [[vitamin B12 deficiency|vitamin B<sub>12</sub> deficiency]], and can be measured clinically as an increased serum [[methylmalonic acid]] (MMA) concentration. The MUT function is necessary for proper [[myelin]] synthesis. Based on animal research, it is thought that the increased methylmalonyl-CoA hydrolyzes to form methylmalonate (methylmalonic acid), a neurotoxic dicarboxylic acid, causing neurological deterioration.
[[Methionine synthase]], coded by ''MTR'' gene, is a methyltransferase enzyme which uses the MeB<sub>12</sub> and reaction type 2 to transfer a methyl group from [[5-methyltetrahydrofolate]] to [[homocysteine]], thereby generating [[tetrahydrofolate]] (THF) and [[methionine]]. This functionality is lost in [[vitamin B12 deficiency|vitamin B<sub>12</sub> deficiency]], resulting in an increased [[homocysteine]] level and the trapping of [[folate]] as 5-methyl-tetrahydrofolate, from which THF (the active form of folate) cannot be recovered. THF plays an important role in DNA synthesis, so reduced availability of THF results in ineffective production of cells with rapid turnover, in particular red blood cells, and also intestinal wall cells which are responsible for absorption. THF may be regenerated via MTR or may be obtained from fresh folate in the diet. Thus all of the DNA synthetic effects of B<sub>12</sub> deficiency, including the [[megaloblastic anemia]] of [[pernicious anemia]], resolve if sufficient dietary folate is present. Thus the best-known "function" of B<sub>12</sub> (that which is involved with DNA synthesis, cell-division, and anemia) is actually a [[:wikt:facultative|facultative]] function which is mediated by B<sub>12</sub>-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-H<sub>4</sub>-MPT, coenzyme M methyltransferase.
</div>
<div lang="en" dir="ltr" class="mw-content-ltr">
==生理学==
==Physiology==
{{Anchor|Physiology}}
===Absorption===
===吸収===
Vitamin B<sub>12</sub> is absorbed by a B<sub>12</sub>-specific transport proteins or via passive diffusion. Transport-mediated absorption and tissue delivery is a complex process involving three transport proteins: [[haptocorrin]] (HC), [[intrinsic factor]] (IF) and [[transcobalamin II]] (TC2), and respective membrane receptor proteins. HC is present in saliva. As vitamin-containing food is digested by [[hydrochloric acid]] and [[pepsin]] secreted into the stomach, HC binds the vitamin and protected it from acidic degradation. Upon leaving the stomach the hydrochloric acid of the [[chyme]] is neutralized in the [[duodenum]] by [[sodium bicarbonate|bicarbonate]], and pancreatic proteases release the vitamin from HC, making it available to be bound by IF, which is a protein secreted by gastric [[parietal cell]]s in response to the presence of food in the stomach. IF delivers the vitamin to receptor proteins [[cubilin]] and [[amnionless]], which together form the [[cubam]] receptor in the distal [[ileum]]. The receptor is specific to the IF-B<sub>12</sub> complex, and so will not bind to any vitamin content that is not bound to IF.
Investigations into the intestinal absorption of B<sub>12</sub> confirm that the upper limit of absorption per single oral dose is about 1.5{{nbsp}}µg, with 50% efficiency. In contrast, the passive diffusion process of B<sub>12</sub> absorption — normally a very small portion of total absorption of the vitamin from food consumption — may exceed the haptocorrin- and IF-mediated absorption when oral doses of B<sub>12</sub> are very large, with roughly 1% efficiency. Thus, dietary supplement B<sub>12</sub> supplementation at 500 to 1000{{nbsp}}µg per day allows [[pernicious anemia]] and certain other defects in B<sub>12</sub> absorption to be treated with daily oral megadoses of B<sub>12</sub> without any correction of the underlying absorption defects.
After the IF/B<sub>12</sub> complex binds to cubam the complex is disassociated and the free vitamin is transported into the [[portal circulation]]. The vitamin is then transferred to TC2, which serves as the circulating plasma transporter, Hereditary defects in production of TC2 and its receptor may produce functional deficiencies in B<sub>12</sub> and infantile [[megaloblastic anemia]], and abnormal B<sub>12</sub> related biochemistry, even in some cases with normal blood B<sub>12</sub> levels. For the vitamin to serve inside cells, the TC2-B<sub>12</sub> complex must bind to a cell receptor protein and be [[endocytosis|endocytosed]]. TC2 is degraded within a [[lysosome]], and free B<sub>12</sub> is released into the cytoplasm, where it is transformed into the bioactive coenzyme by cellular enzymes.
</div>
<div lang="en" dir="ltr" class="mw-content-ltr">
====Malabsorption====
====Malabsorption====
[[Antacid]] drugs that neutralize stomach acid and drugs that block acid production (such as [[proton-pump inhibitor]]s) will inhibit absorption of B<sub>12</sub> by preventing release from food in the stomach. Other causes of B12 malabsorption include [[intrinsic factor]] deficiency, [[pernicious anemia]], [[bariatric surgery]] pancreatic insufficiency, obstructive jaundice, tropical sprue and celiac disease, and radiation enteritis of the distal ileum. Age can be a factor. Elderly people are often [[achlorhydria|achlorhydric]] due to reduced stomach parietal cell function, and thus have an increased risk of B<sub>12</sub> deficiency.
How fast B<sub>12</sub> levels change depends on the balance between how much B<sub>12</sub> is obtained from the diet, how much is secreted and how much is absorbed. The total amount of vitamin B<sub>12</sub> stored in the body is about 2–5{{nbsp}}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 B<sub>12</sub> excretion; most of the B<sub>12</sub> secreted in the bile is recycled via [[enterohepatic circulation]]. Excess B<sub>12</sub> beyond the blood's binding capacity is typically excreted in urine. Owing to the extremely efficient enterohepatic circulation of B<sub>12</sub>, the liver can store 3 to 5 years' worth of vitamin B<sub>12</sub>; therefore, nutritional deficiency of this vitamin is rare in adults in the absence of malabsorption disorders. In the absence of enterohepatic reabsorption, only months to a year of vitamin B<sub>12</sub> are stored.
Vitamin B<sub>12</sub> through its involvement in one-carbon metabolism plays a key role in [[Induced pluripotent stem cell|cellular reprogramming]] and tissue regeneration and epigenetic regulation. Cellular reprogramming is the process by which somatic cells can be converted to a pluripotent state. Vitamin B<sub>12</sub> levels affect the histone modification [[H3K36me3]], which suppresses illegitimate transcription outside of [[Promoter (genetics)|gene promoters]]. Mice undergoing in vivo reprogramming were found to become depleted in B<sub>12</sub> and show signs of [[methionine]] starvation while supplementing reprogramming mice and cells with B<sub>12</sub> increased reprogramming efficiency, indicating a cell-intrinsic effect.
</div>
<div lang="en" dir="ltr" class="mw-content-ltr">
==合成==
==Synthesis==
{{Anchor|Synthesis}}
===Biosynthesis===
===生合成===
{{Main|Cobalamin biosynthesis}}
{{Main/ja|Cobalamin biosynthesis/ja}}
Vitamin B<sub>12</sub> is derived from a [[tetrapyrrole|tetrapyrrolic structural framework]] created by the enzymes [[Porphobilinogen deaminase|deaminase]] and [[uroporphyrinogen III synthase|cosynthetase]] which transform [[aminolevulinic acid]] via [[porphobilinogen]] and [[hydroxymethylbilane]] to [[uroporphyrinogen III]]. The latter is the first [[macrocycle|macrocyclic]] intermediate common to [[heme]], [[chlorophyll]], [[siroheme]] and B<sub>12</sub> itself. Later steps, especially the incorporation of the additional methyl groups of its structure, were investigated using <sup>13</sup>C [[isotopic labelling|methyl-labelled]] [[S-adenosyl methionine]]. It was not until a [[genetic engineering|genetically engineered]] strain of ''[[Pseudomonas denitrificans]]'' was used, in which eight of the genes involved in the biosynthesis of the vitamin had been [[gene expression|overexpressed]], that the complete sequence of [[methylation]] and other steps could be determined, thus fully establishing all the intermediates in the pathway.
Species from the following [[Genus|genera]] and the following individual species are known to synthesize B<sub>12</sub>: ''[[Propionibacterium]] shermanii'', ''[[Pseudomonas]]'' ''denitrificans'', ''[[Streptomyces]]'' ''griseus'', ''[[Acetobacterium]]'', ''[[Aerobacter]]'', ''[[Agrobacterium]]'', ''[[Alcaligenes]]'', ''[[Azotobacter]]'', ''[[Bacillus]]'', ''[[Clostridium]]'', ''[[Corynebacterium]]'', ''[[Flavobacterium]]'', ''[[Lactobacillus]]'', ''[[Micromonospora]]'', ''[[Mycobacterium]]'', ''[[Nocardia]]'', ''[[Proteus (bacterium)|Proteus]]'',
''[[Rhizobium]]'', ''[[Salmonella]]'', ''[[Serratia]]'', ''[[Streptococcus]]'' and ''[[Xanthomonas]]''.
</div>
<div lang="en" dir="ltr" class="mw-content-ltr">
===工業用===
===Industrial===
ビタミンB<sub>12</sub>の工業的生産は、選ばれた微生物の[[Fermentation (biochemistry)/ja|発酵]]によって達成される。かつて[[fungus/ja|真菌]]であると考えられていた''[[fungus/ja|ストレプトマイセス・グリセウス]]''は、長年ビタミンB<sub>12</sub>の商業的供給源であった。今日では、''[[Pseudomonas denitrificans/ja|Pseudomonas denitrificans]]'と''[[Propionibacterium freudenreichii/ja|Propionibacterium freudenreichii]]'の亜種'''shermanii'''がより一般的に使用されている。これらは収量を高めるために特別な条件下で栽培される。[[:en:Rhone-Poulenc|Rhone-Poulenc]]社は''P. denitrificans''を遺伝子操作することで収量を向上させた。''[[Propionibacterium/ja|プロピオニバクテリウム]]''は、[[exotoxin/ja|外毒素]]や[[endotoxin/ja|内毒素]]を産生せず、アメリカの[[Food and Drug Administration/ja|食品医薬品局]]から一般に安全と認められている（[[GRAS/ja|GRAS]]ステータスを付与されている）。
Industrial production of B<sub>12</sub> is achieved through [[Fermentation (biochemistry)|fermentation]] of selected microorganisms. ''[[Streptomyces griseus]]'', a bacterium once thought to be a [[fungus]], was the commercial source of vitamin B<sub>12</sub> for many years. The species ''[[Pseudomonas denitrificans]]'' and ''[[Propionibacterium freudenreichii]]'' subsp. ''shermanii'' are more commonly used today. These are grown under special conditions to enhance yield. [[Rhone-Poulenc]] improved yield via genetic engineering ''P. denitrificans''. ''[[Propionibacterium]]'', the other commonly used bacteria, produce no [[exotoxin]]s or [[endotoxin]]s and are generally recognized as safe (have been granted [[GRAS]] status) by the [[Food and Drug Administration]] of the United States.
The complete laboratory [[vitamin B12 total synthesis|synthesis of B<sub>12</sub>]] was achieved by [[Robert Burns Woodward]] and [[Albert Eschenmoser]] in 1972. The work required the effort of 91 postdoctoral fellows (mostly at Harvard) and 12 PhD students (at [[ETH Zurich]]) from 19 nations. The synthesis constitutes a formal total synthesis, since the research groups only prepared the known intermediate cobyric acid, whose chemical conversion to vitamin B<sub>12</sub> was previously reported. This synthesis of vitamin B<sub>12</sub> is of no practical consequence due to its length, taking 72 chemical steps and giving an overall chemical yield well under 0.01%. Although there have been sporadic synthetic efforts since 1972, the Eschenmoser–Woodward synthesis remains the only completed (formal) total synthesis.
Between 1849 and 1887, [[Thomas Addison]] described a case of [[pernicious anemia]], [[William Osler]] and William Gardner first described a case of neuropathy, Hayem described large red cells in the peripheral blood in this condition, which he called "giant blood corpuscles" (now called [[macrocyte]]s), [[Paul Ehrlich]] identified [[megaloblasts]] in the bone marrow, and [[Ludwig Lichtheim]] described a case of [[myelopathy]].
</div>
<div lang="en" dir="ltr" class="mw-content-ltr">
===抗貧血食品としてのレバーの同定===
===Identification of liver as an anti-anemia food===
1920年代、[[:en:George Whipple|George Whipple]]は、生の[[liver/ja|レバー]]を大量に摂取することが、犬の失血性貧血を最も速やかに治癒させるようであることを発見し、レバーを食べることが悪性貧血を治療するかもしれないという仮説を立てた。[[:en:Edwin Cohn|エドウィン・コーン]]は、悪性貧血の治療に天然の肝臓製品の50倍から100倍の効力がある肝臓エキスを調製した。[[:en:William Bosworth Castle|ウィリアム・キャッスル]]は、胃液に「内在因子」が含まれていることを証明し、この因子が肉の摂取と組み合わさると、悪性貧血の状態でもビタミンが吸収されることを示した。1934年、ジョージ・ウィップルは[[:en:William P. Murphy|ウィリアム・P・マーフィー]]、[[:en:George Minot|ジョージ・マイノット]]と共に、後にビタミンB<sub>12</sub>を多量に含むことが判明した濃縮肝臓を用いた悪性貧血の効果的な治療法の発見により、1934年の[[:en:Nobel Prize in Physiology or Medicine|ノーベル生理学・医学賞]]を受賞した。
During the 1920s, [[George Whipple]] discovered that ingesting large amounts of raw [[liver]] seemed to most rapidly cure the anemia of blood loss in dogs, and hypothesized that eating liver might treat pernicious anemia. [[Edwin Cohn]] prepared a liver extract that was 50 to 100 times more potent in treating pernicious anemia than the natural liver products. [[William Bosworth Castle|William Castle]] demonstrated that gastric juice contained an "intrinsic factor" which when combined with meat ingestion resulted in absorption of the vitamin in this condition. In 1934, George Whipple shared the 1934 [[Nobel Prize in Physiology or Medicine]] with [[William P. Murphy]] and [[George Minot]] for discovery of an effective treatment for pernicious anemia using liver concentrate, later found to contain a large amount of vitamin B<sub>12</sub>.
</div>
<div lang="en" dir="ltr" class="mw-content-ltr">
===活性化合物の同定===
===Identification of the active compound===
米国農務省酪農局に勤務していた[[:en:Mary Shaw Shorb|Mary Shaw Shorb]]は、ヨーグルトやその他の培養乳製品の製造に使用される細菌株''Lactobacillus lactis'' Dorner（LLD）の研究を任された。LLDの培地には肝臓エキスが必要だった。Shorbは、同じ肝臓エキスが悪性貧血の治療に使われていることを知っており（彼女の義父はこの病気で亡くなっていた）、LLDを活性化合物を同定するためのアッセイ法として開発できると結論づけた。メリーランド大学在学中、彼女は[[Merck & Co.|メルク社]]から少額の助成金を受け、同社の[[:en:Karl Folkers|Karl Folkers]]と共同でLLDアッセイ法を開発した。これによって「LLD因子」が細菌の増殖に不可欠であることが特定された。ショーブ、フォルカー、そして[[:en:University of Cambridge|ケンブリッジ大学]]の[[:en:Alexander R. Todd|アレクサンダー・R・トッド]]は、LLDアッセイを用いて肝臓抽出液から抗悪性貧血因子を抽出し、精製してビタミンB<sub>12</sub>と命名した。1955年、トッドはビタミンの構造解明に貢献した。分子の完全な[[Analytical chemistry/ja|化学構造]]は[[:en:Dorothy Hodgkin|ドロシー・ホジキン]]によって[[Crystallography/ja|結晶学]]データに基づいて決定され、1955年に発表された。ホジキンはその後、[[insulin/ja|インスリン]]の構造を解読した。
While working at the Bureau of Dairy Industry, U.S. Department of Agriculture, [[Mary Shaw Shorb]] was assigned work on the bacterial strain ''Lactobacillus lactis'' Dorner (LLD), which was used to make yogurt and other cultured dairy products. The culture medium for LLD required liver extract. Shorb knew that the same liver extract was used to treat pernicious anemia (her father-in-law had died from the disease), and concluded that LLD could be developed as an assay method to identify the active compound. While at the University of Maryland she received a small grant from [[Merck & Co.|Merck]], and in collaboration with [[Karl Folkers]] from that company, developed the LLD assay. This identified "LLD factor" as essential for the bacteria's growth. Shorb, Folker and [[Alexander R. Todd]], at the [[University of Cambridge]], used the LLD assay to extract the anti-pernicious anemia factor from liver extracts, purify it, and name it vitamin B<sub>12</sub>. In 1955, Todd helped elucidate the structure of the vitamin. The complete [[Analytical chemistry|chemical structure]] of the molecule was determined by [[Dorothy Hodgkin]] based on [[Crystallography|crystallographic]] data and published in 1955 for which, and for other crystallographic analyses, she was awarded the Nobel Prize in Chemistry in 1964. Hodgkin went on to decipher the structure of [[insulin]].
George Whipple, George Minot and William Murphy were awarded the Nobel Prize in 1934 for their work on the vitamin. Three other Nobel laureates, Alexander R. Todd (1957), Dorothy Hodgkin (1964) and Robert Burns Woodward (1965) made important contributions to its study.
Industrial production of vitamin B<sub>12</sub> is achieved through [[Fermentation (biochemistry)|fermentation]] of selected microorganisms. As noted above, the completely synthetic laboratory synthesis of B12 was achieved by Robert Burns Woodward and Albert Eschenmoser in 1972, though this process has no commercial potential, requiring more than 70 steps and having a yield well below 0.01%.
</div>
<div lang="en" dir="ltr" class="mw-content-ltr">
==社会と文化==
==Society and culture==
{{Anchor|Society and culture}}
In the 1970s, John A. Myers, a physician residing in Baltimore, developed a program of injecting vitamins and minerals intravenously for various medical conditions. The formula included {{value|1000|u=μg}} of cyanocobalamin. This came to be known as the [[Myers' cocktail]]. After his death in 1984, other physicians and naturopaths took up prescribing "intravenous micro-nutrient therapy" with unsubstantiated health claims for treating fatigue, low energy, stress, anxiety, migraine, depression, immunocompromised, promoting weight loss and more. However, other than a report on case studies there are no benefits confirmed in the scientific literature. Healthcare practitioners at clinics and spas prescribe versions of these intravenous combination products, but also intramuscular injections of just vitamin B<sub>12</sub>. A Mayo Clinic review concluded that there is no solid evidence that vitamin B<sub>12</sub> injections provide an energy boost or aid weight loss.
There is evidence that for elderly people, physicians often repeatedly prescribe and administer cyanocobalamin injections inappropriately, evidenced by the majority of subjects in one large study either having had normal serum concentrations or had not been tested prior to the injections.
