Folate/ja

Folic acid

Clinical data
Pronunciation	/ˈfoʊlɪk, ˈfɒlɪk/
Trade names	Folicet, Folvite
Other names	Wills factor, FA, N-(4-{[(2-amino-4-oxo-1,4-dihydropteridin-6-yl)methyl]amino}benzoyl)-L-glutamic acid, pteroyl-L-glutamic acid, folacin, vitamin B9; formerly, vitamin Bc and vitamin M
AHFS/Drugs.com	Monograph
MedlinePlus	a682591
License data	US DailyMed: Folic acid
Pregnancy category	AU: A
Routes of administration	口から, 筋肉内, 静脈内, 皮下
ATC code	B03BB01 (WHO) V04CX02 (WHO) B03AE02 (WHO) B03AE01 (WHO) B03BB51 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) / S2 US: ℞-only / OTC
Pharmacokinetic data
Bioavailability	50–100%
Metabolism	Liver/ja
Excretion	Urine
Identifiers
IUPAC name (2S)-2-[[4-[(2-Amino-4-oxo-1H-pteridin-6-yl)methylamino]benzoyl]amino]pentanedioic acid
CAS Number	59-30-3 as salt: 6484-89-5
PubChem CID	6037
IUPHAR/BPS	4563
DrugBank	DB00158 as salt: DBSALT001918
ChemSpider	5815 as salt: 21512
UNII	935E97BOY8 as salt: 9P9W8GGU78
KEGG	D00070 as salt: D07985
ChEBI	CHEBI:27470
ChEMBL	ChEMBL1622
PDB ligand	FOL (PDBe, RCSB PDB)
Chemical and physical data
Formula	C19H19N7O6
Molar mass	441.404 g·mol−1
3D model (JSmol)	Interactive image
Density	1.6±0.1 g/cm3
Melting point	250 °C (482 °F) (decomposition)
Solubility in water	1.6mg/L (25 °C)
SMILES n1c2C(=O)NC(N)=Nc2ncc1CNc3ccc(cc3)C(=O)N[C@H](C(O)=O)CCC(O)=O
InChI InChI=1S/C19H19N7O6/c20-19-25-15-14(17(30)26-19)23-11(8-22-15)7-21-10-3-1-9(2-4-10)16(29)24-12(18(31)32)5-6-13(27)28/h1-4,8,12,21H,5-7H2,(H,24,29)(H,27,28)(H,31,32)(H3,20,22,25,26,30)/t12-/m0/s1 Key:OVBPIULPVIDEAO-LBPRGKRZSA-N

葉酸は、ビタミンB₉やフォラシンとも呼ばれ、ビタミンB群の1つである。体内で葉酸に変換される製造された葉酸は、加工時や保存時に安定性が高いため、栄養補助食品や食品強化に用いられる。葉酸は、体内でDNAとRNAを作り、細胞分裂に必要なアミノ酸を代謝するのに必要である。葉酸は人体で作ることができないため、食事から摂取する必要があり、必須栄養素である。多くの食品に自然に含まれている。米国における推奨される成人の1日の葉酸摂取量は、食品または栄養補助食品から400マイクログラムである。

葉酸の形態の葉酸は、葉酸欠乏症によって引き起こされる貧血の治療に用いられる。葉酸はまた、胎児の神経管欠損症（NTDs）のリスクを減らすために、妊娠中の女性がサプリメントとして使用する。妊娠初期の低レベルが、NTDを持つ赤ちゃんの半数以上の原因であると考えられている。80カ国以上が、NTDの発生率を低下させるための対策として、特定の食品に葉酸を義務的または自主的に強化している。比較的多量の葉酸を長期的に補給すると、脳卒中のリスクがわずかに低下し、前立腺がんのリスクが上昇する。大量の葉酸補給は、ビタミンB₁₂欠乏症を隠してしまう懸念がある。

葉酸を十分に摂取しないと、葉酸欠乏症になることがある。その結果、赤血球が異常に大きくなる貧血の一種になることがある。症状としては、疲労感、動悸、息切れ、舌のただれ、皮膚や髪の色の変化などがある。小児の葉酸欠乏症は、食事からの摂取が不十分だと1ヵ月以内に発症することがある。

葉酸は1931年から1943年にかけて発見された。WHOの必須医薬品リストに掲載されている。> 2021年には、米国で77番目に多く処方された医薬品であり、8 万回以上の処方があった。葉酸」という言葉は、ラテン語のfolium（葉を意味する）に由来しており、深緑色の葉野菜に含まれていたためである。

定義

葉酸ファミリーの化学構造

葉酸（ビタミンB₉）は、テトラヒドロ葉酸（活性型）、メチルテトラヒドロ葉酸（血中に含まれる主要型）、メテニルテトラヒドロ葉酸、フォリン酸、フォラシン、プテロイルグルタミン酸などを含む、葉酸およびその関連化合物の多くの形態を指す。歴史的な名称には、L. casei因子、ビタミンB_c、ビタミンMなどがある。

葉酸(folate)と葉酸(folic acid)という用語は、文脈によってやや異なる意味を持つが、互換的に用いられることもある。有機化学の分野では、葉酸(falate)は葉酸(folic acid)の共役塩基を指す。生化学の分野では、葉酸(folate)は葉酸(folic acid)に関連し、葉酸を含む生物学的に活性な化合物の一群を指す。栄養学の分野では、葉酸(folate)という用語は栄養補助食品として使用される製造された葉酸(folic acid)のために予約されているのに対し、葉酸(folic acid)は天然源から得られる葉酸に関連する必須栄養素のファミリーである。

化学的には、葉酸は3つの異なる化学部分が結合したものである。プテリン（2-アミノ-4-ヒドロキシ-プテリジン）複素環環は、p-アミノベンゾイル基とメチレン橋で結合しており、この基はアミド結合を介してグルタミン酸またはポリグルタミン酸のいずれかと結合している。プテリジン環のN5窒素原子および／またはp-アミノベンゾイル基のN10窒素原子には、様々な酸化状態の炭素1単位が結合していてもよい。

Health effects

Folate is especially important during periods of frequent cell division and growth, such as infancy and pregnancy. Folate deficiency hinders DNA synthesis and cell division, affecting hematopoietic cells and neoplasms the most because of their greater frequency of cell division. RNA transcription and subsequent protein synthesis are less affected by folate deficiency, as the mRNA can be recycled and used again (as opposed to DNA synthesis, where a new genomic copy must be created).

Birth defects

Deficiency of folate in pregnant women has been implicated in neural tube defects (NTDs), with an estimate of 300,000 cases worldwide prior to the implementation in many countries of mandatory food fortification. NTDs occur early in pregnancy (first month), therefore women must have abundant folate upon conception and for this reason there is a recommendation that any woman planning to become pregnant consume a folate-containing dietary supplement before and during pregnancy. The Center for Disease Control and Prevention (CDC) recommends a daily amount of 400 micrograms of folic acid for the prevention of NTDs. Compliance with this recommendation is not complete, and many women become pregnant without this being a planned pregnancy, or may not realize that they are pregnant until well into the first trimester, which is the critical period for reducing risk of NTDs. Countries have implemented either mandatory or voluntary food fortification of wheat flour and other grains, or else have no such program and depend on public health and healthcare practitioner advice to women of childbearing age. A meta-analysis of global birth prevalence of spina bifida showed that when mandatory fortification was compared to countries with voluntary fortification or no fortification program, there was a 30% reduction in live births with spina bifida. Some countries reported a greater than 50% reduction. The United States Preventive Services Task Force recommends folic acid as the supplement or fortification ingredient, as forms of folate other than folic acid have not been studied.

A meta-analysis of folate supplementation during pregnancy reported a 28% lower relative risk of newborn congenital heart defects. Prenatal supplementation with folic acid did not appear to reduce the risk of preterm births. One systematic review indicated no effect of folic acid on mortality, growth, body composition, respiratory, or cognitive outcomes of children from birth to 9 years old.

Fertility

Folate contributes to spermatogenesis. In women, folate is important for oocyte quality and maturation, implantation, placentation, fetal growth and organ development.

Heart disease

One meta-analysis reported that multi-year folic acid supplementation, in amounts in most of the included clinical trials at higher than the upper limit of 1,000 μg/day, reduced the relative risk of cardiovascular disease by a modest 4%. Two older meta-analyses, which would not have incorporated results from newer clinical trials, reported no changes to the risk of cardiovascular disease.

Stroke

The absolute risk of stroke with supplementation decreases from 4.4% to 3.8% (a 10% decrease in relative risk). Two other meta-analyses reported a similar decrease in relative risk. Two of these three were limited to people with pre-existing cardiovascular disease or coronary heart disease. The beneficial result may be associated with lowering circulating homocysteine concentration, as stratified analysis showed that risk was reduced more when there was a larger decrease in homocysteine. The effect was also larger for the studies that were conducted in countries that did not have mandatory grain folic acid fortification. The beneficial effect was larger in the subset of trials that used a lower folic acid supplement compared to higher.

Cancer

Chronically insufficient intake of folate may increase the risk of colorectal, breast, ovarian, pancreatic, brain, lung, cervical, and prostate cancers.

Early after fortification programs were implemented, high intakes were theorized to accelerate the growth of preneoplastic lesions that could lead to cancer, specifically colon cancer. Subsequent meta-analyses of the effects of low versus high dietary folate, elevated serum folate, and supplemental folate in the form of folic acid have reported at times conflicting results. Comparing low to high dietary folate showed a modest but statistically significant reduced risk of colon cancer. For prostate cancer risk, comparing low to high dietary folate showed no effect. A review of trials that involved folic acid dietary supplements reported a statistically significant 24% increase in prostate cancer risk. It was shown that supplementation with folic acid at 1,000 to 2,500 μg/day – the amounts used in many of the cited supplement trials – would result in higher concentrations of serum folate than what is achieved from diets high in food-derived folate. The second supplementation review reported no significant increase or decrease in total cancer incidence, colorectal cancer, other gastrointestinal cancer, genitourinary cancer, lung cancer or hematological malignancies in people who were consuming folic acid supplements. A third supplementation meta-analysis limited to reporting only on colorectal cancer incidence showed that folic acid treatment was not associated with colorectal cancer risk.

Anti-folate chemotherapy

Folate is important for cells and tissues that divide rapidly. Cancer cells divide rapidly, and drugs that interfere with folate metabolism are used to treat cancer. The antifolate drug methotrexate is often used to treat cancer because it inhibits the production of the active tetrahydrofolate (THF) from the inactive dihydrofolate (DHF). However, methotrexate can be toxic, producing side effects such as inflammation in the digestive tract that make eating normally more difficult. Bone marrow depression (inducing leukopenia and thrombocytopenia) and acute kidney and liver failure have been reported.

Folinic acid, under the drug name leucovorin, a form of folate (formyl-THF), can help "rescue" or reverse the toxic effects of methotrexate. Folic acid supplements have little established role in cancer chemotherapy. The supplement of folinic acid in people undergoing methotrexate treatment is to give less rapidly dividing cells enough folate to maintain normal cell functions. The amount of folate given is quickly depleted by rapidly dividing (cancer) cells, so this does not negate the effects of methotrexate.

Neurological disorders

Conversion of homocysteine to methionine requires folate and vitamin B₁₂. Elevated plasma homocysteine and low folate are associated with cognitive impairment, dementia and Alzheimer's disease. Supplementing the diet with folic acid and vitamin B₁₂ lowers plasma homocysteine. However, several reviews reported that supplementation with folic acid alone or in combination with other B vitamins did not prevent development of cognitive impairment nor slow cognitive decline.

A 2017 meta-analysis found that the relative risk of autism spectrum disorders was reduced by 23% when the maternal diet was supplemented with folic acid during pregnancy. Subset analysis confirmed this among Asian, European and American populations.

Some evidence links a shortage of folate with clinical depression. Limited evidence from randomized controlled trials showed using folic acid in addition to selective serotonin reuptake inhibitors (SSRIs) may have benefits. Research found a link between depression and low levels of folate. The exact mechanisms involved in the development of schizophrenia and depression are not entirely clear, but the bioactive folate, methyltetrahydrofolate (5-MTHF), a direct target of methyl donors such as S-adenosyl methionine (SAMe), recycles the inactive dihydrobiopterin (BH₂) into tetrahydrobiopterin (BH₄), the necessary cofactor in various steps of monoamine synthesis, including that of dopamine and serotonin. BH₄ serves a regulatory role in monoamine neurotransmission and is required to mediate the actions of most antidepressants.

Folic acid, B₁₂ and iron

A complex interaction occurs between folic acid, vitamin B₁₂, and iron. A deficiency of folic acid or vitamin B₁₂ may mask the deficiency of iron; so when taken as dietary supplements, the three need to be in balance.

Malaria

Some studies show iron–folic acid supplementation in children under five may result in increased mortality due to malaria; this has prompted the World Health Organization to alter their iron–folic acid supplementation policies for children in malaria-prone areas, such as India.

Metabolism

The biological activity of folate in the body depends upon dihydrofolate reductase action in the liver which converts folate into tetrahydrofolate (THF). This action is rate-limiting in humans leading to elevated blood concentrations of unmetabolized folic acid when consumption from dietary supplements and fortified foods nears or exceeds the U.S. Tolerable Upper Intake Level of 1,000 μg per day.

Biosynthesis

Animals, including humans, cannot synthesize folate and therefore must obtain folate from their diet. All plants and fungi and certain protozoa, bacteria, and archaea can synthesize folate de novo through variations on the same biosynthetic pathway. The folate molecule is synthesized from pterin pyrophosphate, para-aminobenzoic acid, and glutamate through the action of dihydropteroate synthase and dihydrofolate synthase. Pterin is in turn derived in a series of enzymatically catalyzed steps from guanosine triphosphate (GTP), while para-aminobenzoic acid is a product of the shikimate pathway.

Bioactivation

Biotransformation of folic acid into folinic acids where R = para-aminobenzoate-glutamate

All of the biological functions of folic acid are performed by THF and its methylated derivatives. Hence folic acid must first be reduced to THF. This four electron reduction proceeds in two chemical steps both catalyzed by the same enzyme, dihydrofolate reductase. Folic acid is first reduced to dihydrofolate and then to tetrahydrofolate. Each step consumes one molecule of NADPH (biosynthetically derived from vitamin B₃) and produces one molecule of NADP.

A one-carbon (1C) methyl group is added to tetrahydrofolate through the action of serine hydroxymethyltransferase (SHMT) to yield 5,10-methylenetetrahydrofolate (5,10-CH₂-THF). This reaction also consumes serine and pyridoxal phosphate (PLP; vitamin B₆) and produces glycine and pyridoxal. A second enzyme, methylenetetrahydrofolate dehydrogenase (MTHFD2) oxidizes 5,10-methylenetetrahydrofolate to an iminium cation which in turn is hydrolyzed to produce 5-formyl-THF and 10-formyl-THF. This series of reactions using the β-carbon atom of serine as the carbon source provide the largest part of the one-carbon units available to the cell.

Alternative carbon sources include formate which by the catalytic action of formate–tetrahydrofolate ligase adds a 1C unit to THF to yield 10-formyl-THF. Glycine, histidine, and sarcosine can also directly contribute to the THF-bound 1C pool.

Drug interference

A number of drugs interfere with the biosynthesis of THF from folic acid. Among them are the antifolate dihydrofolate reductase inhibitors such as the antimicrobial, trimethoprim, the antiprotozoal, pyrimethamine and the chemotherapy drug methotrexate, and the sulfonamides (competitive inhibitors of 4-aminobenzoic acid in the reactions of dihydropteroate synthetase).

Valproic acid, one of the most commonly prescribed epilepsy treatment drugs, also used to treat certain psychological conditions such as bipolar disorder, is a known inhibitor of folic acid, and as such, has been shown to cause birth defects, including neural tube defects, plus increased risk for children having cognitive impairment and autism. There is evidence that folate consumption is protective.

Function

Tetrahydrofolate's main function in metabolism is transporting single-carbon groups (i.e., a methyl group, methylene group, or formyl group). These carbon groups can be transferred to other molecules as part of the modification or biosynthesis of a variety of biological molecules. Folates are essential for the synthesis of DNA, the modification of DNA and RNA, the synthesis of methionine from homocysteine, and various other chemical reactions involved in cellular metabolism. These reactions are collectively known as folate-mediated one-carbon metabolism.

DNA synthesis

Main articles: Purine metabolism and Pyrimidine metabolism

Folate derivatives participate in the biosynthesis of both purines and pyrimidines.

Formyl folate is required for two of the steps in the biosynthesis of inosine monophosphate, the precursor to GMP and AMP. Methylenetetrahydrofolate donates the C1 center required for the biosynthesis of dTMP (2′-deoxythymidine-5′-phosphate) from dUMP (2′-deoxyuridine-5′-phosphate). The conversion is catalyzed by thymidylate synthase.

Vitamin B₁₂ activation

Simplified schematic diagram of the folate methionine cycle

Methyl-THF converts vitamin B₁₂ to methyl-B₁₂ (methylcobalamin). Methyl-B₁₂ converts homocysteine, in a reaction catalyzed by homocysteine methyltransferase, to methionine. A defect in homocysteine methyltransferase or a deficiency of B₁₂ may lead to a so-called "methyl-trap" of THF, in which THF converts to methyl-THF, causing a deficiency in folate. Thus, a deficiency in B₁₂ can cause accumulation of methyl-THF, mimicking folate deficiency.

Dietary recommendations

Because of the difference in bioavailability between supplemented folic acid and the different forms of folate found in food, the dietary folate equivalent (DFE) system was established. One DFE is defined as 1 μg of dietary folate. 1 μg of folic acid supplement counts as 1.7 μg DFE. The reason for the difference is that when folic acid is added to food or taken as a dietary supplement with food it is at least 85% absorbed, whereas only about 50% of folate naturally present in food is absorbed.

National Institutes of Health (U.S.) nutritional recommendations
μg DFE per day for RDA, μg folic acid for Tolerable upper intake levels (UL)

Age	Infants		Children and adults		Pregnant women		Lactating women
	(AI)	(UL)	(RDA)	(UL)	(RDA)	(UL)	(RDA)	(UL)
0–6 months	65	None set	–	–	–	–	–	–
7–12 months	80	None set	–	–	–	–	–	–
1–3 years	–	–	150	300	–	–	–	–
4–8 years	–	–	200	400	–	–	–	–
9–13 years	–	–	300	600	–	–	–	–
14–18	–	–	400	800	600	800	500	800
19+	–	–	400	1000	600	1000	500	1000

The U.S. Institute of Medicine defines Estimated Average Requirements (EARs), Recommended Dietary Allowances (RDAs), Adequate Intakes (AIs), and Tolerable upper intake levels (ULs) – collectively referred to as Dietary Reference Intakes (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 the same as in United States. For women and men over age 18 the PRI is set at 330 μg/day. PRI for pregnancy is 600 μg/day, for lactation 500 μg/day. For children ages 1–17 years the PRIs increase with age from 120 to 270 μg/day. These values differ somewhat from the U.S. RDAs. The United Kingdom's Dietary Reference Value for folate, set by the Committee on Medical Aspects of Food and Nutrition Policy in 1991, is 200 μg/day for adults.

Safety

The risk of toxicity from folic acid is low because folate is a water-soluble vitamin and is regularly removed from the body through urine. One potential issue associated with high doses of folic acid is that it has a masking effect on the diagnosis of pernicious anaemia due to vitamin B₁₂ deficiency, and may even precipitate or exacerbate neuropathy in vitamin B12-deficient individuals. This evidence justified development of a UL for folate. In general, ULs are set for vitamins and minerals when evidence is sufficient. The adult UL of 1,000 μg for folate (and lower for children) refers specifically to folic acid used as a supplement, as no health risks have been associated with high intake of folate from food sources. The EFSA reviewed the safety question and agreed with United States that the UL be set at 1,000 μg. The Japan National Institute of Health and Nutrition set the adult UL at 1,300 or 1,400 μg depending on age.

Reviews of clinical trials that called for long-term consumption of folic acid in amounts exceeding the UL have raised concerns. Excessive amounts derived from supplements are more of a concern than that derived from natural food sources and the relative proportion to vitamin B₁₂ may be a significant factor in adverse effects. One theory is that consumption of large amounts of folic acid leads to detectable amounts of unmetabolized folic acid circulating in blood because the enzyme dihydrofolate reductase that converts folic acid to the biologically active forms is rate limiting. Evidence of a negative health effect of folic acid in blood is not consistent, and folic acid has no known cofactor function that would increase the likelihood of a causal role for free folic acid in disease development. However, low vitamin B₁₂ status in combination with high folic acid intake, in addition to the previously mentioned neuropathy risk, appeared to increase the risk of cognitive impairment in the elderly. Long-term use of folic acid dietary supplements in excess of 1,000 μg/day has been linked to an increase in prostate cancer risk.

Food labeling

For U.S. food and dietary supplement labeling purposes the amount in a serving is expressed as a percent of Daily Value (%DV). For folate labeling purposes 100% of the Daily Value was 400 μg. As of the 27 May 2016 update, it was kept unchanged at 400 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.

European Union regulations require that labels declare energy, protein, fat, saturated fat, carbohydrates, sugars, and salt. Voluntary nutrients may be shown if present in significant amounts. Instead of Daily Values, amounts are shown as percent of Reference Intakes (RIs). For folate, 100% RI was set at 200 μg in 2011.

Deficiency

Main article: Folate deficiency

Folate deficiency can be caused by unhealthy diets that do not include enough vegetables and other folate-rich foods; diseases in which folates are not well absorbed in the digestive system (such as Crohn's disease or celiac disease); some genetic disorders that affect levels of folate; and certain medicines (such as phenytoin, sulfasalazine, or trimethoprim-sulfamethoxazole). Folate deficiency is accelerated by alcohol consumption, possibly by interference with folate transport.

Folate deficiency may lead to glossitis, diarrhea, depression, confusion, anemia, and fetal neural tube and brain defects. Other symptoms include fatigue, gray hair, mouth sores, poor growth, and swollen tongue. Folate deficiency is diagnosed by analyzing a complete blood count (CBC) and plasma vitamin B₁₂ and folate levels. A serum folate of 3 μg/L or lower indicates deficiency. Serum folate level reflects folate status, but erythrocyte folate level better reflects tissue stores after intake. An erythrocyte folate level of 140 μg/L or lower indicates inadequate folate status. Serum folate reacts more rapidly to folate intake than erythrocyte folate.

Since folate deficiency limits cell division, erythropoiesis (production of red blood cells) is hindered. This leads to megaloblastic anemia, which is characterized by large, immature red blood cells. This pathology results from persistently thwarted attempts at normal DNA replication, DNA repair, and cell division, and produces abnormally large red cells called megaloblasts (and hypersegmented neutrophils) with abundant cytoplasm capable of RNA and protein synthesis, but with clumping and fragmentation of nuclear chromatin. Some of these large cells, although immature (reticulocytes), are released early from the marrow in an attempt to compensate for the anemia. Both adults and children need folate to make normal red and white blood cells and prevent anemia, which causes fatigue, weakness, and inability to concentrate.

Increased homocysteine levels suggest tissue folate deficiency, but homocysteine is also affected by vitamin B₁₂ and vitamin B₆, renal function, and genetics. One way to differentiate between folate deficiency and vitamin B₁₂ deficiency is by testing for methylmalonic acid (MMA) levels. Normal MMA levels indicate folate deficiency and elevated MMA levels indicate vitamin B₁₂ deficiency. Elevated MMA levels may also be due to the rare metabolic disorder combined malonic and methylmalonic aciduria (CMAMMA).

Folate deficiency is treated with supplemental oral folic acid of 400 to 1000 μg per day. This treatment is very successful in replenishing tissues, even if deficiency was caused by malabsorption. People with megaloblastic anemia need to be tested for vitamin B₁₂ deficiency before treatment with folic acid, because if the person has vitamin B₁₂ deficiency, folic acid supplementation can remove the anemia, but can also worsen neurologic problems. Cobalamin (vitamin B₁₂) deficiency may lead to folate deficiency, which, in turn, increases homocysteine levels and may result in the development of cardiovascular disease or birth defects.

Sources

The United States Department of Agriculture, Agricultural Research Service maintains a food composition database from which folate content in hundreds of foods can be searched as shown in the table. The Food Fortification Initiative lists all countries in the world that conduct fortification programs, and within each country, what nutrients are added to which foods, and whether those programs are voluntary or mandatory. In the US, mandatory fortification of enriched breads, cereals, flours, corn meal, pastas, rice, and other grain products began in January 1998. As of 2023, 140 countries require food fortification with one or more vitamins, with folate required in 69 countries. The most commonly fortified food is wheat flour, followed by maize flour and rice. From country to country, added folic acid amounts range from 0.4 to 5.1 mg/kg, but the great majority are in a more narrow range of 1.0 to 2.5 mg/kg, i.e. 100–250 μg/100g. Folate 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 be lost from foods boiled in water. For foods that are normally consumed cooked, values in the table are for folate naturally occurring in cooked foods.

Plant sources	Amount as Folate (μg / 100 g)
Peanuts	246
Sunflower seed kernels	238
Lentils	181
Chickpeas	172
Asparagus	149
Spinach	146
Lettuce	136
Peanuts (oil-roasted)	125
Soybeans	111
Broccoli	108
Walnuts	98

Plant sources	Amount as Folate (μg / 100 g)
Peanut butter	92
Hazelnuts	88
Avocados	81
Beets	80
Kale	65
Bread (not fortified)	65
Cabbage	46
Red bell peppers	46
Cauliflower	44
Tofu	29
Potatoes	28

Animal sources	Amount as Folate (μg / 100 g)
Chicken liver	578
Calf liver	331
Cheese	20–60
Chicken eggs	44
Salmon	35
Chicken	12
Beef	12
Pork	8
Yogurt	8–11
Milk, whole	5
Butter, salted	3

食品の栄養強化

「Food fortification/ja」も参照

葉酸強化とは、小麦粉やその他の食品に合成葉酸を添加することで、国民の血中葉酸濃度を高め、公衆衛生を促進することを意図している。葉酸は、加工や保存の際に安定性が高いことから使用されている。葉酸不足と神経管欠損症との関連性が発見された後、世界中の政府や保健機関が、妊娠を希望する女性に対する葉酸サプリメントの推奨を行った。神経管は妊娠の最初の4週間で、多くの女性が妊娠に気づく前に閉鎖するため、やがて多くの国が食品強化プログラムの義務化を決定した。二分脊椎の世界的な出生有病率のメタアナリシスによると、義務的な栄養強化プログラムを実施している国と、任意的な栄養強化プログラムを実施していない国を比較した場合、二分脊椎の出生数が30％減少し、50％以上減少した国もあったと報告されている。

Folic acid is added to grain products in more than 80 countries, either as required or voluntary fortification, and these fortified products make up a significant source of the population's folate intake. Fortification is controversial, with issues having been raised concerning individual liberty, as well as the theorized health concerns described in the Safety section. In the U.S., there is concern that the federal government mandates fortification but does not provide monitoring of potential undesirable effects of fortification. The Food Fortification Initiative lists all countries in the world that conduct fortification programs, and within each country, what nutrients are added to which foods. The most commonly mandatory fortified vitamin – in 62 countries – is folate; the most commonly fortified food is wheat flour.

オーストラリアとニュージーランド

オーストラリアとニュージーランドは、2007年に食品基準オーストラリア・ニュージーランドを通じて小麦粉の強化に共同で合意した。必要量はパン100gあたり葉酸135 μgとされた。オーストラリアは2009年にこのプログラムを実施した。ニュージーランドも2009年からパンの葉酸強化（オーガニックと無着色を除く）を計画していたが、研究が進むまで待つことにした。ベーカリー協会と緑の党は、強制的な強化は「大量医薬品」であるとして反対していた。食品安全大臣ケイト・ウィルキンソンは、2009年7月に強化の決定を見直し、葉酸の過剰摂取とがんのリスク増加との関連性の主張に反対する理由として挙げた。2012年には、遅れていた義務的な強化プログラムが撤回され、パンの強化目標50％の達成を目指した自主的なプログラムに変更された。

カナダ

カナダの公衆衛生の取り組みは、出産適齢期のすべての女性に対する葉酸補給の重要性の認識を促進し、社会的弱者である女性グループに実際的な葉酸支援を提供することによって社会経済的不平等を減少させることに重点を置いていた。葉酸食品強化は1998年に義務化され、強化小麦粉および未調理の穀類100 グラムあたり150 μgの葉酸の強化が義務付けられた。カナダにおける神経管欠損症の発生率に対する葉酸強化の結果は良好であり、神経管欠損症の有病率が46％減少した。減少の大きさは強化前の神経管欠損症の発生率に比例しており、強化前にカナダで見られた神経管欠損症の発生率の地理的なばらつきは本質的に取り除かれていた。

イギリス

食品基準庁は葉酸の強化を推奨し、小麦粉は鉄で強化されているが、小麦粉の葉酸強化は義務ではなく任意で認められている。英国を拠点とする著者らによる2018年のレビューでは、神経管欠損症のリスクを低減する手段として、義務的な強化の再考が強く推奨されている。

アメリカ

米国をはじめとする多くの国では、小麦粉に葉酸を添加している。トウモロコシ粉や米にも葉酸を添加している国もある。

1996年、アメリカ食品医薬品局（FDA）は、濃縮パン、シリアル、小麦粉、コーンミール、パスタ、米、その他の穀物製品に葉酸を添加することを義務付ける規則を発表した。この規定は1998年1月1日に施行され、特に新生児の神経管先天異常のリスクを減らすことを目的としていた。葉酸の添加量が不十分であるとの懸念が表明された。

強化プログラムによって、葉酸摂取量は1日あたり70～130μg増加すると予想されていたが、実際にはその2倍近い増加が見られた。これは、多くの食品が必要量を160～175％上回って強化されていることに起因している可能性がある。高齢者の多くは、1日の葉酸摂取量に400 μgを追加するサプリメントを摂取している。これは、人口の70～80％が血中に検出可能なレベルの未代謝葉酸を有しており、葉酸サプリメントや栄養強化の結果であるため懸念される。しかし、食品強化によって達成された血中濃度では、葉酸には補因子の機能が知られていないため、遊離葉酸が疾患発症に因果的な役割を果たす可能性は高まらない。

米国国立保健統計センターは、年2回、全米健康栄養調査（NHANES）を実施し、米国の成人と子供の健康と栄養状態を調査している。一部の結果は「What We Eat In America」として報告されている。2013-2014年の調査では、20歳以上の成人について、男性は食品からの葉酸摂取が平均249 μg/日、強化食品の摂取による葉酸摂取が207 μg/日、合わせて601 μg/日の食事性葉酸等価物（葉酸1マイクログラムが食品葉酸1.7 μgとカウントされるためDFEs）を摂取していると報告された。女性の場合は、それぞれ199、153、459 μg/日である。これは、強化によって葉酸摂取量が当初の予測よりも大幅に増加し、成人の半数以上がRDAの400 μg（DFEとして）を超えて摂取していることを意味する。それでも、妊娠中のRDAである600 μg/日を超えている妊婦は半数以下である。

葉酸強化以前、米国では毎年約4,100件の妊娠が神経管欠損症の影響を受けていた。疾病管理予防センターは2015年、FDAの義務として穀物ベースの食品に葉酸を添加して以来、神経管欠損症の発生率が35％低下したと報告した。これは、予防されたNTD罹患出生児の年間総直接コストに換算すると、約5億800万ドルの節約になる。

歴史

「ビタミン」を参照

1920年代、科学者たちは葉酸欠乏と貧血は同じ状態であると考えていた。1931年、研究者ルーシー・ウィルスは、妊娠中の貧血を予防するために必要な栄養素として葉酸を特定するきっかけとなった重要な観察を行った。ウィルスは貧血がビール酵母で回復することを実証した。1930年代後半には、葉酸がビール酵母に含まれる補正物質であることが確認された。葉酸は1941年にハーシェル・K・ミッチェル、エスモンド・E・スネル、ロジャー・J・ウィリアムズによってほうれん草の葉から抽出することで初めて単離された。葉緑素はラテン語のfolium（葉を意味する）に由来する。歴史的な名称には、L. casei因子、ヒヨコで行われた研究にちなんだビタミンB_c、サルで行われた研究にちなんだビタミンMなどがある。

ボブ・ストークスタッドは1943年に純粋な結晶形の葉酸を単離し、アメリカン・サイアナミッド社のレダール研究所で働いていたときに、その化学構造を決定することができた。1945年に純粋な結晶形の葉酸を得るというこの歴史的な研究プロジェクトは、ニューヨーク州パールリバーのレダール研究所で、イエラプラガダ・サブバロウ研究部長の監督指導のもと、「葉酸ボーイズ」と呼ばれるチームによって行われた。この研究はその後、抗葉酸アミノプテリンの合成につながり、1948年にシドニー・ファーバーによって小児白血病の治療に使用された。

1950年代から1960年代にかけて、科学者たちは葉酸の生化学的作用機序を発見し始めた。1960年、研究者たちは葉酸欠乏と神経管欠損症のリスクを関連づけた。1990年代後半、米国とカナダ政府は、公教育プログラムや葉酸サプリメントの入手可能性にもかかわらず、出産適齢期の女性が1日の葉酸推奨量を満たすにはまだ課題があると判断し、この2カ国が葉酸強化プログラムを実施した。2018年12月現在、62カ国が葉酸の食品強化を義務付けている。

動物

獣医師は、葉酸欠乏症の危険性が指摘された場合、犬猫の検査を行うことがある。外分泌膵不全の猫は、犬よりも血清葉酸が低い可能性がある。口唇裂や口蓋裂のリスクがある犬種では、食事性葉酸サプリメントにより発症率が有意に低下した。

外部リンク

生化学リンク

• Folate biosynthesis (early stages)
• Folate biosynthesis (later stages)
• Folate coenzymes
• C₁ metabolism with folate
• Formylation, hydroxymethylation and methylation using folate