View source for Vitamin B12/ja

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{{About/ja|ビタマー・ファミリー|individual forms/ja|hydroxocobalamin/ja|and|cyanocobalamin/ja|and|methylcobalamin/ja|and|adenosylcobalamin/ja|
}}
{{DISPLAYTITLE:ビタミンB{{ssub|12}}}}
{{Infobox drug
| image = Cobalamin skeletal.svg
| width = 200
| caption = コバラミン類の一般的な[[skeletal formula/ja|骨格式]]である。
| image2            = Cyanocobalamin-from-xtal-3D-st-noH.png
| width2            =
| alt2              =
| caption2          = 結晶構造に基づく[[cyanocobalamin/ja|シアノコバラミン]]（R = CN）の[[Ball-and-stick model/ja|スティックモデル]]

<!--Clinical data-->
| tradename =
| Drugs.com = {{drugs.com|monograph|vitamin_b12}}
| MedlinePlus = a605007
| DailyMedID = Vitamin_b12
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| routes_of_administration = [[Oral administration/ja|口から]], 舌下, [[intravenous/ja]] (IV), [[intramuscular/ja]] (IM), 経鼻
| ATC_prefix = B03
| ATC_suffix = BA01

| legal_AU = <!-- Unscheduled / S2 / S4 / S8 -->
| legal_UK = OTC
| legal_US = OTC

<!--Pharmacokinetic data-->
| bioavailability = 回腸の遠位半分で容易に吸収される。
| protein_bound = 特定の[[transcobalamins/ja|トランスコバラミン]]血漿タンパク質への結合性が非常に高い。<br />[[hydroxocobalamin/ja|ヒドロキソコバラミン]]の結合性はシアノコバラミンよりわずかに高い。
| metabolism = [[Liver/ja]]
| elimination_half-life = 約6日間<br />（肝臓では400日間）
| excretion = [[Kidney/ja]]

<!--Identifiers-->
| CAS_number = 68-19-9
| PubChem = 184933
| DrugBank = DB00115
| ChemSpiderID = 10469504
| UNII = P6YC3EG204
| KEGG = D00166
| ChEMBL = 2110563
| synonyms = Vitamin B12, vitamin B-12, cobalamin

<!--Chemical data-->
| IUPAC_name = α-(5,6-Dimethylbenzimidazolyl)cobamidcyanide
| C=63 | H=88 | Co=1 | N=14 | O=14 | P=1
| smiles = NC(=O)C[C@@]8(C)[C@H](CCC(N)=O)C=2/N=C8/C(/C)=C1/[C@@H](CCC(N)=O)[C@](C)(CC(N)=O)[C@@](C)(N1[Co+]C#N)[C@@H]7/N=C(C(\C)=C3/N=C(/C=2)C(C)(C)[C@@H]3CCC(N)=O)[C@](C)(CCC(=O)NCC(C)OP([O-])(=O)O[C@@H]6[C@@H](CO)O[C@H](n5cnc4cc(C)c(C)cc45)[C@@H]6O)[C@H]7CC(N)=O
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C62H90N13O14P.CN.Co/c1-29-20-39-40(21-30(29)2)75(28-70-39)57-52(84)53(41(27-76)87-57)89-90(85,86)88-31(3)26-69-49(83)18-19-59(8)37(22-46(66)80)56-62(11)61(10,25-48(68)82)36(14-17-45(65)79)51(74-62)33(5)55-60(9,24-47(67)81)34(12-15-43(63)77)38(71-55)23-42-58(6,7)35(13-16-44(64)78)50(72–42)32(4)54(59)73–56;1–2;/h20-21,23,28,31,34-37,41,52-53,56-57,76,84H,12-19,22,24-27H2,1-11H3,(H15,63,64,65,66,67,68,69,71,72,73,74,77,78,79,80,81,82,83,85,86);;/q;;+2/p-2/t31?,34-,35-,36-,37+,41-,52-,53-,56-,57+,59-,60+,61+,62+;;/m1../s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = RMRCNWBMXRMIRW-WYVZQNDMSA-L
}}

'''ビタミンB<sub>12</sub>'''は、'''コバラミン'''としても知られ、[[metabolism/ja|代謝]]に関与する水溶性の[[vitamin/ja|ビタミン]]である。8種類の[[B vitamins/ja|ビタミンB群]]の1つである。[[DNA synthesis/ja|DNA合成]]の[[cofactor (biochemistry)/ja|補因子]]として、また[[fatty acid metabolism/ja|脂肪酸]]と[[amino acid metabolism/ja|アミノ酸代謝]]の両方で使用する動物に必要である。[[nervous system/ja|神経系]]では[[myelinogenesis/ja|ミエリンの合成]]、[[circulatory system/ja|循環器系]]では[[bone marrow/ja|骨髄]]における[[red blood cell/ja|赤血球]]の成熟に重要な役割を果たす。植物はコバラミンを必要とせず、コバラミンに依存しない酵素で反応を行う。

ビタミンB<sub>12</sub>はすべてのビタミンの中で最も化学的に複雑であり、ヒトにとっては動物由来の食品またはサプリメントから摂取しなければならない唯一のビタミンである。ビタミンB<sub>12</sub>を合成できるのは一部の[[archaea/ja|古細菌]]と[[bacteria/ja|バクテリア]]だけである。ビタミンB<sub>12</sub>欠乏症は、特に動物性食品の消費量が少ない集団に広く見られる症状である。これは、社会経済的地位の低さ、倫理的配慮、[[veganism/ja|菜食主義]]などのライフスタイルの選択など、さまざまな理由によるものである。

ビタミンB<sub>12</sub>を含む食品には、肉、[[clam/ja|貝]]、[[Liver (food)/ja|肝臓]]、魚、[[poultry/ja|鶏肉]]、[[Egg as food/ja|卵]]、[[dairy product/ja|乳製品]]などがある。多くの[[breakfast cereal/ja|朝食用シリアル]]はこのビタミンで[[food fortification/ja|食品強化]]されている。[[Vitamin B12 deficiency/ja|ビタミンB<sub>12</sub>欠乏症]]の治療と予防には、[[dietary supplement/ja|サプリメント]]や医薬品が利用できる。通常は口から摂取するが、欠乏症の治療には[[intramuscular injection/ja|筋肉注射]]で投与することもある。

ビタミンB<sub>12</sub>欠乏は、妊娠中、幼児、高齢者に大きな影響を及ぼし、栄養失調のために中低開発国でより一般的である。先進国におけるビタミンB<sub>12</sub>欠乏の最も一般的な原因は、吸収が起こるためには食物由来のB<sub>12</sub>と結合していなければならない[[Intrinsic factor/ja|胃内在因子]]（IF）の損失による[[malabsorption/ja|吸収障害]]である。第二の主な原因は、加齢に伴う[[gastric acid/ja|胃酸]]産生の低下である（[[archlorhydria/ja|無胃酸症]]）。同じ理由で、[[proton-pump inhibitors/ja|プロトンポンプ阻害薬]]や[[H2 blocker/ja|H<sub>2</sub>遮断薬]]などの制酸剤を長期間使用している人はリスクが高くなる。

ベジタリアンや菜食主義者の食事では、栄養補助食品を摂取しない限り、十分なB<sub>12</sub>を摂取できないことがある。欠乏症は、手足の[[neuropathy/ja|神経障害]]や、[[pernicious anemia/ja|悪性貧血]]と呼ばれる血液疾患、赤血球が異常に大きくなる[[Megaloblastic anemia/ja||貧血の一種]]と呼ばれる血液疾患によって特徴づけられることがある。その結果、[[fatigue/ja|疲労感]]、思考力の低下、ふらつき、息切れ、頻繁な[[infection/ja|感染症]]、[[anorexia (symptom)/ja|食欲不振]]、[[paresthesia/ja|手足の知覚異常]]、抑うつ、記憶喪失、錯乱、[[ataxia/ja|歩行困難]]、[[optic neuropathy/ja視神経障害]]、不可逆的な神経損傷、その他多くの症状が現れる。乳児の場合、欠乏を放置すると神経障害や貧血を引き起こす可能性がある。個体内の[[folate/ja|葉酸]]濃度は、ビタミンB<sub>12</sub>欠乏症の病理学的変化や症状の経過に影響を及ぼす可能性がある。妊婦におけるビタミンB<sub>12</sub>欠乏は、自然流産、神経管欠損症などの先天奇形、胎児の脳発達成長障害などのリスク上昇と強く関連している。

ビタミンB<sub>12</sub>は、ビタミンB<sub>12</sub>の欠乏により、血液中の赤血球の数が通常より少なくなる[[autoimmune disorder/ja|自己免疫疾患]]である悪性貧血の結果として発見された。ビタミンを吸収する能力は加齢とともに、特に60歳以上では低下する。
{{TOC limit}}

==定義==
{{Anchor|Definition}}
ビタミンB<sub>12</sub>は[[cobalt/ja|コバルト]]の[[coordination complex/ja|配位錯体]]で、[[corrin/ja|コリン]]配位子の中心を占め、さらに[[benzimidazole/ja|ベンズイミダゾール]]配位子とアデノシル基が結合している。多くの近縁種が知られており、これらは同様の挙動を示し、特にすべてがビタミンとして機能する。この化合物群は「コバラミン」と呼ばれることもある。これらの化合物は類似した分子構造を持ち、それぞれがビタミン欠乏の生体系でビタミン活性を示すことから、[[vitamer/ja|ビタマー]]と呼ばれる。ビタミンの活性は[[coenzyme/ja|補酵素]]としてのもので、酵素触媒反応にその存在が必要であることを意味する。
* [[adenosylcobalamin/ja|アデノシルコバラミン]]
* [[cyanocobalamin/ja|シアノコバラミン]]は、ビタミンB<sub>12</sub>のアデノシル配位子が[[cyanide/ja|シアン化物]]で置換されている。
* [[hydroxocobalamin/ja|ヒドロキソコバラミン]]は、ビタミンB<sub>12</sub>のアデノシル配位子を[[hydroxide/ja|水酸化物]]に置き換えたものである。
* ビタミンB<sub>12</sub>のアデノシル配位子は[[methyl/ja|メチル]]で置換される。

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/ja|サイトゾル]]中の[[methylcobalamin/ja|メチルコバラミン]]と[[mitochondria/ja|ミトコンドリア]]中の[[adenosylcobalamin/ja|アデノシルコバラミン]]である。

シアノコバラミンが栄養補助食品や[[food fortification/ja|食品強化]]に最もよく使われるのは、シアンが分解に対して分子を安定させるからである。メチルコバラミンも栄養補助食品として提供されている。ビタミンB<sub>12</sub>欠乏症の治療にアデノシルコバラミンやメチルコバラミン型を使用する利点はない。

[[Hydroxocobalamin/ja|ヒドロキソコバラミン]]は、ビタミンB<sub>12</sub>欠乏症を治療するために筋肉内に注射することができる。ヒドロキシル基がシアン化物によって置換され、尿中に排泄される無毒のシアノコバラミンが生成されるため、シアン化物中毒を治療する目的で静脈注射することもできる。

"疑似ビタミンB<sub>12</sub>"は、ビタミンに似た構造を持つがビタミン活性を持たない[[corrinoid/ja|コリノイド]]である化合物を指す。偽ビタミンB<sub>12</sub>は、藻類の健康食品である[[Spirulina (dietary supplement)/ja|スピルリナ]]に含まれるコリノイドの大部分である。

==欠乏症==
{{Anchor|Deficiency}}
{{Main/ja|Vitamin B12 deficiency/ja|l1=Vitamin B<sub>12</sub> deficiency/ja}}
ビタミンB<sub>12</sub>欠乏症は、特に脳と神経系に深刻で不可逆的な損傷を引き起こす可能性がある。正常値よりわずかに低いレベルで欠乏すると、[[Fatigue (medical)/ja|疲労]]、脱力感、[[lightheadedness/ja|ふらつき]]、[[dizziness/ja|めまい]]、息苦しさ、頭痛、[[mouth ulcer/ja|口内炎]]、胃のむかつき、食欲低下などのさまざまな症状を引き起こす可能性がある、 歩行困難（ふらつきバランス障害）、筋力低下、[[Depression (mood)/ja|抑うつ]]、[[memory/ja|記憶力]]低下、反射神経低下、錯乱、皮膚の青白さ、[[paresthesia/ja|知覚異常]]など、特に60歳以上の人に多い。ビタミンB<sub>12</sub>欠乏症はまた、[[mania/ja|躁病]]や[[psychosis/ja|精神病]]の症状を引き起こすこともある。

[[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：
# 骨髄前赤芽球癆を伴う[[Anemia/ja|貧血]]（[[megaloblastic anemia/ja|巨赤芽球性貧血]]）。これは[[DNA synthesis/ja|DNA合成]]（特に[[purines/ja|プリン]]と[[thymidine/ja|チミジン]]）の阻害によるものである。
# 消化器症状：軽度の[[diarrhea/ja|下痢]]や[[constipation/ja|便秘]]などの腸管運動の変化、膀胱や腸のコントロールができなくなる。これらは、細胞の入れ替わりが激しい組織部位において、DNA合成の欠陥が複製を阻害するためと考えられている。これは、悪性貧血における胃の[[parietal cell/ja|壁細胞]]に対する[[autoimmune/ja|自己免疫]]攻撃にも起因している可能性がある。[[gastric antral vascular ectasia/ja|胃前庭血管拡張症]]（スイカ胃と呼ばれることもある）と悪性貧血との関連がある。
# 神経学的症状：感覚または運動障害（反射の欠如、振動または軟部触覚の減退）および[[subacute combined degeneration of spinal cord/ja|亜急性脊髄複合変性症]]がある。小児における欠損症状には、[[developmental delay/ja|発達遅延]]、[[developmental regression/ja|退行]]、[[irritability/ja|過敏性]]、[[Abnormal involuntary movements/ja|不随意運動]]、および[[hypotonia/ja|筋緊張低下]]が含まれる。

ビタミンB<sub>12</sub>欠乏症は、最も一般的には吸収不良によって起こるが、摂取量の低下、免疫性胃炎、結合タンパク質の存在低下、特定の医薬品の使用によっても起こる。植物性食品にはビタミン欠乏症を予防するのに十分な量のビタミンが含まれていないため、[[vegan/ja|菜食主義者]]-動物性食品を一切摂取しないことを選択した人々-にはリスクがある。また、[[Vegetarianism/ja|菜食主義者]]-乳製品や卵などの動物性副産物は摂取するが、動物の肉は摂取しない-もリスクがある。ビタミンB<sub>12</sub>欠乏症は、ビタミンB<sub>12</sub>サプリメントを摂取していないか、ビタミン強化食品を摂取していないベジタリアン人口の40％から80％で観察されている。香港とインドでは、菜食主義者の約80％にビタミンB<sub>12</sub>欠乏症が認められている。ベジタリアンと同様に、菜食主義者も栄養補助食品を摂取するか、シリアル、植物性ミルク、[[nutritional yeast/ja|栄養酵母]]などのビタミンB<sub>12</sub>強化食品を常食することでこれを避けることができる。高齢者は、加齢とともに[[stomach acid/ja|胃酸]]の分泌が減少する傾向があり、[[achlorhydria/ja|無胃酸症]]として知られる状態になるため、リスクが高くなる。

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。

===妊娠期、授乳期、幼児期=== 
米国の[[Dietary Reference Intake/ja|推奨食事許容量 (RDA)]]は、妊娠期は{{value|2.6|u=µg/day}}、授乳期は{{value|2.8|u=µg/日}}である。これらの値の決定は、非妊娠女性のRDA{{値|2.4|u=µg/day}}に、妊娠中に胎児に移行する分と母乳中に移行する分を加えたものである。しかし、同じ科学的根拠から、[[:en:European Food Safety Authority|欧州食品安全機関]]（EFSA）は適切摂取量（AI）を、妊娠期は{{value|4.5|u=μg/day}}、授乳期は{{value|5.0|u=μg/day}}としている。妊娠中、[[placenta/ja|胎盤]]はB<sub>12</sub>を濃縮するので、新生児の血清濃度は母親よりも高くなる。より効果的に胎盤に到達するのは最近吸収されたビタミンであるため、母親になる女性が摂取するビタミンは、肝臓組織に含まれるビタミンよりも重要である。

動物性食品をほとんど摂取していない女性、あるいはベジタリアンやビーガンの女性は、動物性食品を多く摂取している女性よりも、妊娠中にビタミン欠乏症になるリスクが高い。この欠乏は貧血を引き起こし、母乳で育てられた乳児がビタミン欠乏症になるリスクも高くなる。ビタミンB<sub>12</sub>は、世界保健機関（WHO）が妊娠中の健康な女性に推奨するサプリメントのひとつではないが、特にベジタリアンやビーガンの食生活を送っている妊娠中の母親には、葉酸と一緒にマルチビタミンにビタミンB<sub>12</sub>を配合することがよく勧められている。

母乳中のビタミン濃度が低いのは、社会経済的地位が低いか、動物性食品の消費量が少ない家庭である。小麦粉やトウモロコシ粉の食品強化プログラムが義務づけられているのは、アフリカを中心とした数カ国だけで、インドには任意の強化プログラムがある。授乳中の母親が摂取するものは、肝組織の含有量よりも、最近吸収されたビタミンがより効果的に母乳に到達することの方が重要である。母乳中のビタミンB<sub>12</sub>は、栄養状態の良い母親でもビタミン欠乏症の母親でも、授乳期間中に減少する。6ヵ月を超える母乳育児は、授乳中の乳児の血清ビタミン状態が低いことを示す強い指標となる。特に、妊娠中にビタミン状態が不良であった場合や、母乳育児中の乳児に与える初期導入食品がビーガンであった場合に当てはまる。

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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.}
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=== Gastric bypass surgery ===
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.
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===Diagnosis===
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.
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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.
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==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.]]
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===Treatment of deficiency===
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.
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===Cyanide poisoning===
For [[cyanide]] poisoning, a large amount of hydroxocobalamin may be given [[intravenously]] and sometimes in combination with [[sodium thiosulfate]].
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==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.
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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).
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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}}.
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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.
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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&nbsp;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]].
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==Sources==
===Bacteria and archaea===
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.
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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>.
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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.
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=== Animal-derived foods ===
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]].
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===Plants and algae===
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.
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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.
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===Fortified foods===
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.
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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.
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Vegan advocacy organizations, among others, recommend that every vegan consume B<sub>12</sub> from either fortified foods or supplements.
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=== Supplements ===
[[File:Methylcobalamin tablets.jpg|thumb|200px|A blister pack of 500 µg methylcobalamin tablets]]
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.
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[[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.
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=== Intramuscular or intravenous injection ===
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.
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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.
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=== 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.
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=== Pseudovitamin-B<sub>12</sub> ===
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.
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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.
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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.
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== Drug interactions ==
===H<sub>2</sub>-receptor antagonists and proton-pump inhibitors===
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.
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===Metformin===
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.
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===Other drugs===
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]].
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==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).
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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]]
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=== 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>.
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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.
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==Biochemistry==
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===Coenzyme function===
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):
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# [[Isomerase]]s
#: 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.
# [[Methyltransferase]]s
#: Methyl (–CH<sub>3</sub>) group transfers between two molecules. These use the MeB<sub>12</sub> (methylcobalamin) form of the vitamin.
# [[Dehalogenase]]s
#: 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>.
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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]]
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[[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.
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[[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.
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==Physiology==
===Absorption===
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.
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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.
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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.
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====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.
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===Storage and excretion===
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.
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=== Cellular reprogramming ===
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.
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==Synthesis==
===Biosynthesis===
{{Main|Cobalamin biosynthesis}}
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.
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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]]''.
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===Industrial===
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.
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The total world production of vitamin B<sub>12</sub> in 2008 was 35,000&nbsp;kg (77,175&nbsp;lb).
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===Laboratory===
{{Main|Vitamin B12 total synthesis|l1=Vitamin B<sub>12</sub> total synthesis}}
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.
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==History==
{{Further|Vitamin#History}}
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===Descriptions of deficiency effects===
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]].
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===Identification of liver as an anti-anemia food===
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>.
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===Identification of the active compound===
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]].
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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.
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===Commercial production===
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%.
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==社会と文化==
{{Anchor|Society and culture}}
1970年代、ボルチモア在住の医師ジョン・A・マイヤーズは、さまざまな病状に対してビタミンとミネラルを静脈注射するプログラムを開発した。その処方には{{value|1000|u=μg}}のシアノコバラミンが含まれていた。これは[[Myers' cocktail/ja|マイヤーズのカクテル]]として知られるようになった。1984年にマイヤーズが亡くなった後、他の医師や自然療法家たちが、疲労、エネルギー低下、ストレス、不安、偏頭痛、うつ病、免疫不全、体重減少などを治療するために、根拠のない健康強調表示をした「微量栄養素点滴療法」を処方するようになった。しかし、症例研究の報告以外には、科学的文献で確認された効果はない。診療所やスパの開業医は、これらのビタミンB<sub>12</sub>を配合した点滴製剤を処方しているが、ビタミンB<sub>12</sub>だけの筋肉注射も行っている。メイヨークリニックのレビューでは、ビタミンB<sub>12</sub>注射がエネルギー増強や体重減少を助けるという確かな証拠はないと結論づけている。

高齢者では、医師が不適切なシアノコバラミン注射を繰り返し処方・投与しているという証拠がある。これは、ある大規模な研究において、被験者の大半が血清濃度が正常であったか、注射前の検査を受けていなかったことからも明らかである。

== こちらも参照 ==
* [[Adenosylcobalamin/ja]]
* [[Cobalamin biosynthesis/ja]]
* [[Cyanocobalamin/ja]]
* [[Hydroxocobalamin/ja]]
* [[Methylcobalamin/ja]]
* [[Vitamin/ja]]

==さらに読む==
* {{cite journal |vauthors=Gherasim C, Lofgren M, Banerjee R |title=Navigating the B(12) road: assimilation, delivery, and disorders of cobalamin |journal=J. Biol. Chem. |volume=288 |issue=19 |pages=13186–13193 |date=May 2013 |pmid=23539619 |pmc=3650358 |doi=10.1074/jbc.R113.458810 |doi-access=free }}

== 外部リンク ==
* {{MeSH name|Cyanocobalamin}}

{{Vitamins/ja}}
{{Tetrapyrroles/ja}}
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[[Category:Vitamin B12| ]]
[[Category:B vitamins]]
[[Category:Cofactors]]
[[Category:Organocobalt compounds]]
[[Category:Cobalt(III) compounds]]
[[Category:Cobalt(II) compounds]]