ビオチン
Biotin/ja
ビオチン（ビタミンB7またはビタミンHとも呼ばれる）は、ビタミンB群の1つである。ビオチンは、主に脂肪、炭水化物、アミノ酸の利用に関連し、ヒトと他の生物の両方で、代謝プロセスの広い範囲に関与している。ビオチンという名前は、ドイツ語のBiotinから借用したもので、古代ギリシャ語のβίοτος (bíotos; 'life')と接尾辞"-in"（化学では通常'形成'を示すために使用される接尾辞）に由来する。ビオチンは、針のように見える白い結晶性の固体として現れる。
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| Names | |
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| Preferred IUPAC name
5-[(3aS,4S,6aR)-2-Oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentanoic acid | |
| Other names
Vitamin B7
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| Identifiers | |
3D model (JSmol)
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| Properties | |
| C10H16N2O3S | |
| Molar mass | 244.31 g·mol−1 |
| Appearance | White crystalline needles |
| Melting point | 232 to 233 °C (450 to 451 °F; 505 to 506 K) |
| 22 mg/100 mL | |
| Pharmacology | |
| A11HA05 (WHO) | |
| Hazards | |
| NFPA 704 (fire diamond) | |
化学的説明
ビオチンは複素環化合物に分類され、硫黄を含むテトラヒドロチオフェン環とウレイド基が縮合している。前者の環にはC5-カルボン酸側鎖が付加している。N-CO-N-基を含むウレイド環は、カルボキシル化反応において二酸化炭素のキャリアーとして機能する。ビオチンは5つのカルボキシラーゼ酵素の補酵素であり、アミノ酸や脂肪酸の異化、脂肪酸の合成、糖新生に関与する。核クロマチン中のヒストンタンパク質のビオチン化は、クロマチンの安定性と遺伝子発現に関与する。
食事の推奨量
米国医学アカデミーは1998年、多くのビタミンについて食事摂取基準を更新した。その時点では、ほとんどのビタミンに存在する用語である推定平均所要量または推奨食事摂取量を設定するには情報が不十分であった。このような場合、ビオチンの生理学的効果がよりよく理解された後日、AIがより正確な情報によって置き換えられることを理解した上で、学会は適切な摂取量（AI）を設定する。男女ともにビオチンのAIは以下の通りである： 0～6ヵ月児はビオチン5 μg/日、7～12ヵ月児はビオチン6 μg/日、1～3歳児はビオチン8 μg/日、12 ； μg／日、9～13歳は20μg／日、14～18歳は25μg／日、19歳以上は30μg／日である。妊娠中または授乳中の女性のビオチン摂取基準は、それぞれ以下の通りである： 妊娠中の女性（14～50歳）にはビオチン30 μg/日、授乳中の女性（14～50歳）にはビオチン35 μg/日である。オーストラリアとニュージーランドは、米国と同様の基準値を設定している。
また、欧州食品安全機関（EFSA）は、成人については40 μg/日、妊娠中については40 μg/日、授乳中については45 μg/日の値を設定し、AIを特定している。1～17歳の子どもについては、年齢が上がるにつれてAI値は20～35 μg/日と増加する。
安全性
米国医学アカデミーは、ビタミンとミネラルの摂取上限値について、十分なエビデンスがある場合に、その上限値を設定している。しかし、ビオチンについては、ビオチンの大量摂取による悪影響が明らかにされていないため、上限値は設定されていない。EFSAも安全性を検討し、米国と同じ結論に達した。
表示規制
米国の食品および栄養補助食品の表示目的では、1食分の量は1日摂取量のパーセンテージで表される。ビオチンの表示目的では、1日価値の100%は300 μg/日であったが、2016年5月27日付で、適切な摂取量と一致させるために30 μg/日に改定された。更新された表示規制への適合は、年間食品売上高がUS$1,000 万以上の製造業者には2020年1月1日までに、それ以下の製造業者には2021年1月1日までに義務付けられた。新旧の成人一日摂取量の表は基準一日摂取量に掲載されている。
摂取源
| Source | Amount (μg / 100 g) |
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| Chicken liver | 187 |
| Beef liver | 42 |
| Eggs | 21 |
| Egg white | 5.8 |
| Egg yolk | 27 |
| Salmon, canned in water | 5.9 |
| Pork chop | 4.5 |
| Turkey breast | 0.7 |
| Tuna, white, canned | 0.7 |
| Source | Amount (μg / 100 g) |
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| Peanuts, roasted | 17.5 |
| Sunflower seeds, roasted | 7.8 |
| Almonds, roasted | 4.4 |
| Sweet potato | 1.5 |
| Broccoli | 0.9 |
| Tomato | 0.7 |
| Strawberry | 1.5 |
| Avocado | 1.0 |
| Corn, canned | 0.05 |
Biotin is stable at room temperature and is not destroyed by cooking. The dietary biotin intake in Western populations has been estimated to be in the range of 35 to 70 μg/day. Nursing infants ingest about 6 μg/day. Biotin is available in dietary supplements, individually or as an ingredient in multivitamins.
According to the Global Fortification Data Exchange, biotin deficiency is so rare that no countries require that foods be fortified.
Physiology
Biotin is a water-soluble B vitamin. Consumption of large amounts as a dietary supplement results in absorption, followed by excretion into urine as biotin. Consumption of biotin as part of a normal diet results in urinary excretion of biotin and biotin metabolites.
Absorption
Biotin in food is bound to proteins. Digestive enzymes reduce the proteins to biotin-bound peptides. The intestinal enzyme biotinidase, found in pancreatic secretions and in the brush border membranes of all three parts of the small intestine, frees biotin, which is then absorbed from the small intestine. When consumed as a biotin dietary supplement, absorption is nonsaturable, meaning that even very high amounts are absorbed effectively. Transport across the jejunum is faster than across the ileum.
The large intestine microbiota synthesize amounts of biotin estimated to be similar to the amount taken in the diet, and a significant portion of this biotin exists in the free (protein-unbound) form and, thus, is available for absorption. How much is absorbed in humans is unknown, although a review did report that human epithelial cells of the colon in vitro demonstrated an ability to uptake biotin.
Once absorbed, sodium-dependent multivitamin transporter (SMVT) mediates biotin uptake into the liver. SMVT also binds pantothenic acid, so high intakes of either of these vitamins can interfere with transport of the other.
Metabolism and excretion
Biotin catabolism occurs via two pathways. In one, the valeric acid sidechain is cleaved, resulting in bisnorbiotin. In the other pathway, the sulfur is oxidized, resulting in biotin sulfoxide. Urine content is proportionally about half biotin, plus bisnorbiotin, biotin sulfoxide, and small amounts of other metabolites.
Factors that affect biotin requirements
Chronic alcohol use is associated with a significant reduction in plasma biotin. Intestinal biotin uptake also appears to be sensitive to the effect of the anti-epilepsy drugs carbamazepine and primidone. Relatively low levels of biotin have also been reported in the urine or plasma of patients who have had a partial gastrectomy or have other causes of achlorhydria, as well as burn patients, elderly individuals, and athletes. Pregnancy and lactation may be associated with an increased demand for biotin. In pregnancy, this may be due to a possible acceleration of biotin catabolism, whereas, in lactation, the higher demand has yet to be elucidated. Recent studies have shown marginal biotin deficiency can be present in human gestation, as evidenced by increased urinary excretion of 3-hydroxyisovaleric acid, decreased urinary excretion of biotin and bisnorbiotin, and decreased plasma concentration of biotin.
Biosynthesis
Biotin, synthesized in plants, is essential to plant growth and development. Bacteria also synthesize biotin, and it is thought that bacteria resident in the large intestine may synthesize biotin that is absorbed and utilized by the host organism.
Biosynthesis starts from two precursors, alanine and pimeloyl-CoA. These form 7-keto-8-aminopelargonic acid (KAPA). KAPA is transported from plant peroxisomes to mitochondria where it is converted to 7,8-diaminopelargonic acid (DAPA) with the help of the enzyme, BioA. The enzyme dethiobiotin synthetase catalyzes the formation of the ureido ring via a DAPA carbamate activated with ATP, creating dethiobiotin with the help of the enzyme, BioD, which is then converted into biotin which is catalyzed by BioB. The last step is catalyzed by biotin synthase, a radical SAM enzyme. The sulfur is donated by an unusual [2Fe-2S] ferredoxin. Depending on the species of bacteria, Biotin can be synthesized via multiple pathways.
Cofactor biochemistry
The enzyme holocarboxylase synthetase covalently attaches biotin to five human carboxylase enzymes:
- Acetyl-CoA carboxylase alpha (ACC1)
- Acetyl-CoA carboxylase beta (ACC2)
- Pyruvate carboxylase (PC)
- Methylcrotonyl-CoA carboxylase (MCC)
- Propionyl-CoA carboxylase (PCC)
For the first two, biotin serves as a cofactor responsible for transfer of bicarbonate to acetyl-CoA, converting it to malonyl-CoA for fatty acid synthesis. PC participates in gluconeogenesis. MCC catalyzes a step in leucine metabolism. PCC catalyzes a step in the metabolism of propionyl-CoA. Metabolic degradation of the biotinylated carboxylases leads to the formation of biocytin. This compound is further degraded by biotinidase to release biotin, which is then reutilized by holocarboxylase synthetase.
Biotinylation of histone proteins in nuclear chromatin is a posttranslational modification that plays a role in chromatin stability and gene expression.
Deficiency
Primary biotin deficiency, meaning deficiency as a consequence of too little biotin in the diet, is rare, because biotin is contained in so many foods. Subclinical deficiency can cause mild symptoms, such as hair thinning, brittle fingernails, or skin rash, typically on the face.
Aside from inadequate dietary intake (rare), deficiency of biotin can be caused by a genetic disorder that affects biotin metabolism. The most common among these is biotinidase deficiency. Low activity of this enzyme causes a failure to recycle biotin from biocytin. Rarer are carboxylase and biotin transporter deficiences. Neonatal screening for biotinidase deficiency started in the United States in 1984, with many countries now also testing for this genetic disorder at birth. Treatment is lifelong dietary supplement with biotin. If biotinidase deficiency goes untreated, it can be fatal.
Diagnosis
Low serum and urine biotin are not sensitive indicators of inadequate biotin intake. However, serum testing can be useful for confirmation of consumption of biotin-containing dietary supplements, and whether a period of refraining from supplement use is long enough to eliminate the potential for interfering with drug tests. Indirect measures depend on the biotin requirement for carboxylases. 3-Methylcrotonyl-CoA is an intermediate step in the catabolism of the amino acid leucine. In the absence of biotin, the pathway diverts to 3-hydroxyisovaleric acid. Urinary excretion of this compound is an early and sensitive indicator of biotin deficiency.
Deficiency as a result of metabolic disorders
Biotinidase deficiency is a deficiency of the enzyme that recycles biotin, the consequence of an inherited genetic mutation. Biotinidase catalyzes the cleavage of biotin from biocytin and biotinyl-peptides (the proteolytic degradation products of each holocarboxylase) and thereby recycles biotin. It is also important in freeing biotin from dietary protein-bound biotin. Neonatal screening for biotinidase deficiency started in the United States in 1984, which as of 2017 was reported as required in more than 30 countries.
Profound biotinidase deficiency, defined as less than 10% of normal serum enzyme activity, which has been reported as 7.1 nmol/min/mL, has an incidence of 1 in 40,000 to 1 in 60,000, but with rates as high as 1 in 10,000 in countries with high incidence of consanguineous marriages (second cousin or closer). Partial biotinidase deficiency is defined as 10% to 30% of normal serum activity. Incidence data stems from government mandated newborn screening. For profound deficiency, treatment is oral dosing with 5 to 20 mg per day. Seizures are reported as resolving in hours to days, with other symptoms resolving within weeks. Treatment of partial biotinidase deficiency is also recommended even though some untreated people never manifest symptoms. Lifelong treatment with supplemental biotin is recommended for both profound and partial biotinidase deficiency.
Inherited metabolic disorders characterized by deficient activities of biotin-dependent carboxylases are termed multiple carboxylase deficiency. These include deficiencies in the enzymes holocarboxylase synthetase. Holocarboxylase synthetase deficiency prevents the body's cells from using biotin effectively and thus interferes with multiple carboxylase reactions. There can also be a genetic defect affecting the sodium-dependent multivitamin transporter protein.
Biochemical and clinical manifestations of any of these metabolic disorders can include ketolactic acidosis, organic aciduria, hyperammonemia, rash, hypotonia, seizures, developmental delay, alopecia and coma.
Use in biotechnology
Chemically modified versions of biotin are widely used throughout the biotechnology industry to isolate proteins and non-protein compounds for biochemical assays. Because egg-derived avidin binds strongly to biotin with a dissociation constant Kd ≈ 10−15 M, biotinylated compounds of interest can be isolated from a sample by exploiting this highly stable interaction. First, the chemically modified biotin reagents are bound to the targeted compounds in a solution via a process called biotinylation. The choice of which chemical modification to use is responsible for the biotin reagent binding to a specific protein. Second, the sample is incubated with avidin bound to beads, then rinsed, removing all unbound proteins, while leaving only the biotinylated protein bound to avidin. Last, the biotinylated protein can be eluted from the beads with excess free biotin. The process can also utilize bacteria-derived streptavidin bound to beads, but because it has a higher dissociation constant than avidin, very harsh conditions are needed to elute the biotinylated protein from the beads, which often will denature the protein of interest.
Interference with medical laboratory results
When people are ingesting high levels of biotin in dietary supplements, a consequence can be clinically significant interference with diagnostic blood tests that use biotin-streptavidin technology. This methodology is commonly used to measure levels of hormones such as thyroid hormones, and other analytes such as 25-hydroxyvitamin D. Biotin interference can produce both falsely normal and falsely abnormal results. In the US, biotin as a non-prescription dietary supplement is sold in amounts of 1 to 10 mg per serving, with claims for supporting hair and nail health, and as 300 mg per day as a possibly effective treatment for multiple sclerosis (see § Research). Overconsumption of 5 mg/day or higher causes elevated concentration in plasma that interferes with biotin-streptavidin immunoassays in an unpredictable manner. Healthcare professionals are advised to instruct patients to stop taking biotin supplements for 48 h or even up to weeks before the test, depending on the specific test, dose, and frequency of biotin uptake. Guidance for laboratory staff is proposed to detect and manage biotin interference.
History
In 1916, W. G. Bateman observed that a diet high in raw egg whites caused toxic symptoms in dogs, cats, rabbits, and humans.By 1927, scientists such as Margarete Boas and Helen Parsons had performed experiments demonstrating the symptoms associated with "egg-white injury." They had found that rats fed large amounts of egg-white as their only protein source exhibited neurological dysfunction, hair loss, dermatitis, and eventually, death.
In 1936, Fritz Kögl and Benno Tönnis documented isolating a yeast growth factor in a journal article titled "Darstellung von krystallisiertem biotin aus eigelb." (Representation of crystallized biotin from egg yolk). The name biotin derives from the Greek word bios ('to live') and the suffix "-in" (a general chemical suffix used in organic chemistry). Other research groups, working independently, had isolated the same compound under different names. Hungarian scientist Paul Gyorgy began investigating the factor responsible for egg-white injury in 1933 and in 1939, was successful identifying what he called "Vitamin H" (the H represents Haar und Haut, German for 'hair and skin'). Further chemical characterization of vitamin H revealed that it was water-soluble and present in high amounts in the liver. After experiments performed with yeast and Rhizobium trifolii, West and Wilson isolated a compound they called co-enzyme R. By 1940, it was recognized that all three compounds were identical and were collectively given the name: biotin. Gyorgy continued his work on biotin and in 1941 published a paper demonstrating that egg-white injury was caused by the binding of biotin by avidin. Unlike for many vitamins, there is insufficient information to establish a recommended dietary allowance, so dietary guidelines identify an "adequate intake" based on best available science with the understanding that at some later date this will be replaced by more exact information.
Using E. coli, a biosynthesis pathway was proposed by Rolfe and Eisenberg in 1968. The initial step was described as a condensation of pimelyl-CoA and alanine to form 7-oxo-8-aminopelargonic acid. From there, they described three-step process, the last being introducing a sulfur atom to form the tetrahydrothiophene ring.
Research
Multiple sclerosis
High-dose biotin (300 mg/day = 10,000 times adequate intake) has been used in clinical trials for treatment of multiple sclerosis, a demyelinating autoimmune disease. The hypothesis is that biotin may promote remyelination of the myelin sheath of nerve cells, slowing or even reversing neurodegeneration. The proposed mechanisms are that biotin activates acetyl-coA carboxylase, which is a key rate-limiting enzyme during the synthesis of myelin, and by reducing axonal hypoxia through enhanced energy production. Clinical trial results are mixed; a 2019 review concluded that a further investigation of the association between multiple sclerosis symptoms and biotin should be undertaken, whereas two 2020 reviews of a larger number of clinical trials reported no consistent evidence for benefits, and some evidence for increased disease activity and higher risk of relapse.
Hair, nails, skin
In the United States, biotin is promoted as a dietary supplement for strengthening hair and fingernails, though scientific data supporting these outcomes in humans are very weak. A review of the fingernails literature reported brittle nail improvement as evidence from two pre-1990 clinical trials that had administered an oral dietary supplement of 2.5 mg/day for several months, without a placebo control comparison group. There is no more recent clinical trial literature. A review of biotin as treatment for hair loss identified case studies of infants and young children with genetic defect biotin deficiency having improved hair growth after supplementation, but went on to report that "there have been no randomized, controlled trials to prove efficacy of supplementation with biotin in normal, healthy individuals."
The Dietary Supplement Health and Education Act of 1994 states that the US Food and Drug Administration must allow on the product label what are described as "Structure:Function" (S:F) health claims that ingredient(s) are essential for health. For example: Biotin helps maintain healthy skin, hair and nails. If a S:F claim is made, the label must include the disclaimer "This statement has not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease."
動物
牛の場合、ビオチンは蹄の健康に必要である。蹄の問題による跛行は一般的で、牛群の有病率は 10 ～ 35% と推定されている。跛行の結果、食餌消費量の減少、乳量の減少、獣医学的治療費の増加などが起こる。ビオチンを1日20 mg/日の割合で飼料に添加すると、4～6ヶ月後に跛行のリスクが減少する。対照試験のレビューでは、20 mg/日の補給で乳量が4.8％増加したと報告している。考察では、これは蹄の健康が改善された間接的な結果か、乳量への直接的な影響ではないかと推測されている。
馬にとって、慢性的な蹄葉炎、ひび割れた蹄、靴を履くことができない乾燥した脆い蹄といった状態は、一般的な問題である。ビオチンは人気のある栄養補助食品である。馬には1日15～25mg必要であると推奨されている。研究報告によると、ビオチンは既存の蹄の状態を改善するのではなく、新しい蹄角の成長を改善するため、蹄壁が完全に入れ替わるには数ヶ月の補給が必要である。
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外部リンク
Media related to Biotin at Wikimedia Commons
