ビタミンB3

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ビタミンB3
Drug class
ビタミンB3の一種であるニコチンアミドの構造
Class identifiers
Use	ビタミンB3欠乏症
ATC code	A11H
Biological target	enzyme cofactor
Clinical data
Drugs.com	Niacin
External links
MeSH	D009536
Legal status

ビタミンB₃は、口語ではナイアシンと呼ばれ、3種類のビタミンを含むビタマー群である： ナイアシン（ニコチン酸）、ニコチンアミド（ナイアシンアミド）、およびニコチンアミドリボシドである。ビタミンB₃の3つの形態はすべて、体内でニコチンアミドアデニンジヌクレオチド（NAD）に変換される。NADは人間が生きていくために必要なもので、ビタミンB₃かトリプトファンがなければ体内で作ることができない。ニコチンアミドリボシドは2004年にビタミンB₃の一種として同定された。

ナイアシン（栄養素）は、動植物がアミノ酸であるトリプトファンから製造することができる。ナイアシンは様々なホールフードや加工食品から食事中に摂取されるが、強化されたパッケージ食品、肉類、鶏肉、マグロやサケなどの赤身魚に最も多く含まれ、ナッツ類、豆類、種子類に含まれる量は少ない。栄養補助食品としてのナイアシンは、ナイアシン欠乏によって引き起こされる疾患であるペラグラの治療に用いられる。ペラグラの徴候や症状には、皮膚や口の病変、貧血、頭痛、疲労感などがある。多くの国では、小麦粉や他の食用穀物への添加を義務付けており、それによってペラグラのリスクを減らしている。

アミド、ニコチンアミド（ナイアシンアミド）は、補酵素の構成成分である。ニコチンアミドアデニンジヌクレオチド（NAD）とニコチンアミドアデニンジヌクレオチドリン酸（NADP+）の構成成分である。ナイアシンとニコチンアミドはそのビタミン活性において同一であるが、ニコチンアミドはナイアシンのような薬理学的、脂質修飾作用や副作用を持たない、すなわち、ナイアシンが-アミド基をとると、コレステロールを減少させず、潮紅を引き起こさない。ニコチンアミドはナイアシン欠乏症の治療薬として推奨されているが、その理由は、副作用とされる潮紅を起こすことなく、改善量の投与が可能だからである。過去には、このグループはビタミンB₃複合体と緩く呼ばれていた。

作用機序

ニコチンアミドアデニンジヌクレオチド（NAD）は、そのリン酸化変異体ニコチンアミドアデニンジヌクレオチドリン酸（NADP）とともに、DNA修復内の転移反応およびカルシウム動員で利用される。NADはまた、解糖とクレブスサイクルの両方において補酵素として働き、ヒトの代謝において重要な役割を果たしている。

ビタミン欠乏症

詳細は「Pellagra/ja」を参照

ペラグラに罹った男性は、食事中のビタミンB₃の慢性的な不足によって引き起こされる。

食事による重度のビタミンB₃欠乏は、下痢、皮膚の色素沈着と肥厚を伴う日光過敏性皮膚炎（画像参照）、口と舌の炎症、せん妄、痴呆、そして放置すれば死を特徴とするペラグラという病気を引き起こす。一般的な精神症状には、いらいら、集中力の低下、不安、疲労、記憶力の低下、落ち着きのなさ、無気力、抑うつなどがある。欠乏が引き起こす神経変性の生化学的メカニズムはよくわかっていないが、A）神経毒性のトリプトファン代謝物の生成を抑制するためのニコチンアミドアデニンジヌクレオチド（NAD+）の必要性、B）細胞障害を引き起こすミトコンドリアATP生成の阻害； C)ポリ（ADP-リボース）ポリメラーゼ（PARP）経路の活性化。PARPはDNA修復に関与する核内酵素であるが、NAD+がない場合は細胞死につながる。D) 神経保護作用のある脳由来神経栄養因子またはその受容体トロポミオシン受容体キナーゼBの合成の減少、あるいはE) ナイアシン欠乏に直接起因するゲノム発現の変化。

ナイアシン欠乏症は先進国ではほとんど見られず、貧困や栄養失調、慢性的なアルコール中毒による二次的な栄養失調と関連するのが一般的である。また、トウモロコシは消化可能なナイアシンが少ないため、人々がトウモロコシ（とうもろこし）を主食としている地域で起こる傾向がある。ニクスタマリゼーションと呼ばれる調理技術、つまりアルカリ成分で前処理をすることで、トウモロコシ粉や小麦粉を製造する際にナイアシンの生物学的利用能が高まる。このため、トウモロコシをトルティーヤやホミニーとして食べる人は、ナイアシン欠乏症のリスクが少ない。

For treating deficiency, the World Health Organization (WHO) recommends administering niacinamide (i.e. nicotinamide) instead of niacin, to avoid the flushing side effect commonly caused by the latter. Guidelines suggest using 300 mg/day for three to four weeks. Dementia and dermatitis show improvement within a week. Because deficiencies of other B-vitamins may be present, the WHO recommends a multi-vitamin in addition to the niacinamide.

Hartnup disease is a hereditary nutritional disorder resulting in niacin deficiency. It is named after an English family with a genetic disorder that resulted in a failure to absorb the essential amino acid tryptophan, tryptophan being a precursor for niacin synthesis. The symptoms are similar to pellagra, including red, scaly rash and sensitivity to sunlight. Oral niacin or niacinamide is given as a treatment for this condition in doses ranging from 50 to 100 mg twice a day, with a good prognosis if identified and treated early. Niacin synthesis is also deficient in carcinoid syndrome, because of metabolic diversion of its precursor tryptophan to form serotonin.

Measuring vitamin status

Plasma concentrations of niacin and niacin metabolites are not useful markers of niacin status. Urinary excretion of the methylated metabolite N1-methyl-nicotinamide is considered reliable and sensitive. The measurement requires a 24-hour urine collection. For adults, a value of less than 5.8 μmol/day represent deficient niacin status and 5.8 to 17.5 μmol/day represents low. According to the World Health Organization, an alternative mean of expressing urinary N1-methyl-nicotinamide is as mg/g creatinine in a 24-hour urine collection, with deficient defined as <0.5, low 0.5-1.59, acceptable 1.6-4.29, and high >4.3 Niacin deficiency occurs before the signs and symptoms of pellagra appear. Erythrocyte nicotinamide adenine dinucleotide (NAD) concentrations potentially provide another sensitive indicator of niacin depletion, although definitions of deficient, low and adequate have not been established. Lastly, plasma tryptophan decreases on a low niacin diet because tryptophan converts to niacin. However, low tryptophan could also be caused by a diet low in this essential amino acid, so it is not specific to confirming vitamin status.

Dietary recommendations

Dietary recommendations

Australia and New Zealand Age group RDI for niacin (mg NE/day) Upper level of intake Infants 0–6 months 2 mg/d preformed niacin* ND Infants 7–12 months 4 mg/d NE* 1–3 6 10 4–8 8 15 9–13 12 20 14–18 – 30 19+ – 35 Females 14+ 14 – Males 14+ 16 Pregnant females 14–50 18 – Pregnant females 14–18 – 30 Pregnant females 19–50 – 35 Lactating females 14–50 17 – Lactating females 14–18 – 30 Lactating females 19–50 – 35 * Adequate Intake for infants Canada Age group (years) RDA of niacin (mg NE/d) Tolerable upper intake level 0–6 months 2 mg/d preformed niacin* ND 7–12 months 4 mg/d NE* 1–3 6 10 4–8 8 15 9–13 12 20 Females 14–18 14 30 Males 14–18 16 Females 19+ 14 35 Males 19+ 16 Pregnant females <18 18 30 Pregnant females 18–50 18 35 Lactating females <18 17 30 Lactating females 18–50 17 35 European Food Safety Authority Gender Adequate Intake (mg NE/MJ) Females 1.3 Males 1.6 Age (years) Tolerable upper limit of Nicotinic acid (mg/day) Tolerable upper limit of Nicotinamide (mg/day) 1–3 2 150 4–6 3 220 7–10 4 350 11–14 6 500 15–17 8 700 United States Age group RDA for niacin (mg NE/day) Tolerable upper intake level Infants 0–6 months 2* ND** Infants 6–12 months 4* 1–3 6 10 4–8 8 15 9–13 12 20 Females 14–18 14 30 Males 14–18 16 30 Females 19+ 14 35 Males 19+ 16 35 Pregnant females 14–18 18 30 Pregnant females 19–50 18 35 Lactating females 14–18 17 30 Lactating females 19–50 17 35 * Adequate intake for infants, as an RDA has yet to be established ** Not possible to establish; source of intake should be formula and food only

The U.S. Institute of Medicine (renamed National Academy of Medicine in 2015) updated Estimated Average Requirements (EARs) and Recommended Dietary Allowances (RDAs) for niacin in 1998, as well as Tolerable upper intake levels (ULs). In lieu of an RDA, Adequate Intakes (AIs) are identified for populations for which there is not enough evidence to identify a dietary intake level that is sufficient to meet the nutrient requirements of most people. (see table).

The European Food Safety Authority (EFSA) refers to the collective set of information as Dietary Reference Values (DRV), with Population Reference Intake (PRI) instead of RDA, and Average Requirement instead of EAR. For the EU, AIs and ULs have the same definition as in the US, except that units are milligrams per megajoule (MJ) of energy consumed rather than mg/day. For women (including those pregnant or lactating), men and children the PRI is 1.6 mg per megajoule. As the conversion is 1 MJ = 239 kcal, an adult consuming 2390 kilocalories should be consuming 16 mg niacin. This is comparable to US RDAs (14 mg/day for adult women, 16 mg/day for adult men).

ULs are established by identifying amounts of vitamins and minerals that cause adverse effects, and then selecting as an upper limit amounts that are the "maximum daily intake unlikely to cause adverse health effects". Regulatory agencies from different countries do not always agree. For the US, 30 or 35 mg for teenagers and adults, less for children. The EFSA UL for adults is set at 10 mg/day – about one-third of the US value. For all of the government ULs, the term applies to niacin as a supplement consumed as one dose, and is intended as a limit to avoid the skin flush reaction. This explains why for EFSA, the recommended daily intake can be higher than the UL.

Both the DRI and DRV describe amounts needed as niacin equivalents (NE), calculated as 1 mg NE = 1 mg niacin or 60 mg of the essential amino acid tryptophan. This is because the amino acid is utilized to synthesize the 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 niacin labeling purposes 100% of the Daily Value is 16 mg. Prior to May 27, 2016, it was 20 mg, revised to bring it into agreement with the RDA. Compliance with the updated labeling regulations was required by January 1, 2020, for manufacturers with US$10 million or more in annual food sales, and by January 1, 2021, for manufacturers with lower volume food sales. A table of the old and new adult daily values is provided at Reference Daily Intake.

Sources

Niacin is found in a variety of whole and processed foods, including fortified packaged foods, meat from various animal sources, seafoods, and spices. In general, animal-sourced foods provide about 5–10 mg niacin per serving, although dairy foods and eggs have little. Some plant-sourced foods such as nuts, legumes and grains provide about 2–5 mg niacin per serving, although in some grain products this naturally present niacin is largely bound to polysaccharides and glycopeptides, making it only about 30% bioavailable. Fortified food ingredients such as wheat flour have niacin added, which is bioavailable. Among whole food sources with the highest niacin content per 100 grams:

Source	Amount (mg / 100g)
Nutritional yeast Serving = 2 Tbsp (16 g) contains 56 mg	350
Tuna, yellowfin	22.1
Peanuts	14.3
Peanut butter	13.1
Bacon	10.4
Tuna, light, canned	10.1
Salmon	10.0
Turkey depending on what part, how cooked	7-12
Chicken depending on what part, how cooked	7-12

Source	Amount (mg / 100g)
Beef depending on what part, how cooked	4-8
Pork depending on what part, how cooked	4-8
Sunflower seeds	7.0
Tuna, white, canned	5.8
Almonds	3.6
Mushrooms, white	3.6
Cod fish	2.5
Rice, brown	2.5
Hot dogs	2.0

Source	Amount (mg / 100g)
Avocado	1.7
Potato, baked, with skin	1.4
Corn (maize)	1.0
Rice, white	0.5
Kale	0.4
Eggs	0.1
Milk	0.1
Cheese	0.1
Tofu	0.1

Vegetarian and vegan diets can provide adequate amounts if products such as nutritional yeast, peanuts, peanut butter, tahini, brown rice, mushrooms, avocado and sunflower seeds are included. Fortified foods and dietary supplements can also be consumed to ensure adequate intake.

Food preparation

Niacin naturally found in food is susceptible to destruction from high heat cooking, especially in the presence of acidic foods and sauces. It is soluble in water, and so may also be lost from foods boiled in water.

Food fortification

Countries fortify foods with nutrients to address known deficiencies. As of 2020, 54 countries required food fortification of wheat flour with niacin or niacinamide; 14 also mandate fortification of maize flour, and 6 mandate fortification of rice. From country to country, niacin fortification ranges from 1.3 to 6.0 mg/100 g.

As a dietary supplement

In the United States, niacin (the acid) is sold as a non-prescription dietary supplement with a range of 100 to 1000 mg per serving. These products often have a Structure/Function health claim allowed by the US Food & Drug Administration (FDA). An example would be "Supports a healthy blood lipid profile." The American Heart Association (AHA) strongly advises against the use of non-prescription dietary supplement niacin rather than prescription niacin because of potentially serious side effects. For this reason and because the manufacture of dietary supplement niacin is not as well-regulated by the FDA as is prescription niacin, the AHA advises that supplemental niacin only be used under the supervision of a health care professional. More than 30 mg niacin consumed as a dietary supplement can cause skin flushing. Face, arms and chest skin turns a reddish color because of vasodilation of small subcutaneous blood vessels, accompanied by sensations of heat, tingling and itching. These signs and symptoms are typically transient, lasting minutes to hours; they are considered unpleasant rather than toxic.

Toxicity

The daily limit for vitamin B₃ has been set at 35 mg. At daily doses of as low as 30 mg, flushing has been reported, always starting in the face and sometimes accompanied by skin dryness, itching, paresthesia, and headache. Liver toxicity is the most serious toxic reaction and it occurs at doses >2 grams/day. Fulminant hepatitis has been reported at doses between 3-9 grams/day with needs for liver transplantation. Other reactions include glucose intolerance, hyperuricemia, macular edema, and macular cysts.

History

「Pellagra」を参照

Corn (maize) became a staple food in the southeast United States and in parts of Europe. A disease that was characterized by dermatitis of sunlight-exposed skin was described in Spain in 1735 by Gaspar Casal. He attributed the cause to poor diet. In northern Italy it was named pellagra from the Lombard language (agra = holly-like or serum-like; pell = skin). In time, the disease was more closely linked specifically to corn. In the US, Joseph Goldberger was assigned to study pellagra by the Surgeon General of the United States. His studies confirmed a corn-based diet as the culprit, but he did not identify the root cause.

Nicotinic acid was extracted from the liver by biochemist Conrad Elvehjem in 1937. He later identified the active ingredient, referring to it as "pellagra-preventing factor" and the "anti-blacktongue factor." It was also referred to as "vitamin PP", "vitamin P-P" and "PP-factor", all derived from the term "pellagra-preventive factor". In the late 1930s, studies by Tom Douglas Spies, Marion Blankenhorn, and Clark Cooper confirmed that niacin cured pellagra in humans. The prevalence of the disease was greatly reduced as a result.

In 1942, when flour enrichment with nicotinic acid began, a headline in the popular press said "Tobacco in Your Bread." In response, the Council on Foods and Nutrition of the American Medical Association approved of the Food and Nutrition Board's new names niacin and niacin amide for use primarily by non-scientists. It was thought appropriate to choose a name to dissociate nicotinic acid from nicotine, to avoid the perception that vitamins or niacin-rich foods contain nicotine, or that cigarettes contain vitamins. The resulting name niacin was derived from nicotinic acid + vitamin.

J. Laguna and K.J. Carpenter found in 1951, that niacin in corn is biologically unavailable and can be released only in very alkaline lime water of pH 11. This explains why a Latin-American culture that used alkali-treated (nixtamalized) cornmeal to make tortilla was not at risk for niacin deficiency.