Riboflavin
Clinical data | |
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Trade names | Many[1] |
Other names | lactochrome, lactoflavin, vitamin G[2] |
AHFS/Drugs.com | Monograph |
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intravenous | |
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Pharmacokinetic data | |
Elimination half-life | 66 to 84 minutes |
Excretion | Urine |
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JSmol) | |
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Riboflavin, also known as vitamin B2, is a
Riboflavin was discovered in 1920, isolated in 1933, and first synthesized in 1935. In its purified, solid form, it is a water-soluble yellow-orange crystalline powder. In addition to its function as a vitamin, it is used as a food coloring agent. Biosynthesis takes place in bacteria, fungi and plants, but not animals. Industrial synthesis of riboflavin was initially achieved using a chemical process, but current commercial manufacturing relies on fermentation methods using strains of fungi and genetically modified bacteria.
Definition
Riboflavin, also known as vitamin B2, is a water-soluble vitamin and is one of the B vitamins.[3][4][5] Unlike folate and vitamin B6, which occur in several chemically related forms known as vitamers, riboflavin is only one chemical compound. It is a starting compound in the synthesis of the coenzymes flavin mononucleotide (FMN, also known as riboflavin-5'-phosphate) and flavin adenine dinucleotide (FAD). FAD is the more abundant form of flavin, reported to bind to 75% of the number of flavin-dependent protein encoded genes in the all-species genome (the flavoproteome)[6][7] and serves as a co-enzyme for 84% of human-encoded flavoproteins.[6]
In its purified, solid form, riboflavin is a yellow-orange crystalline powder with a slight odor and bitter taste. It is soluble in polar solvents, such as water and aqueous sodium chloride solutions, and slightly soluble in alcohols. It is not soluble in non-polar or weakly polar organic solvents such as chloroform, benzene or acetone.[8] In solution or during dry storage as a powder, riboflavin is heat stable if not exposed to light. When heated to decompose, it releases toxic fumes containing nitric oxide.[8]
Functions
Riboflavin is essential to the formation of two major coenzymes, FMN and FAD.
Redox reactions
Redox reactions are processes that involve the transfer of electrons. The flavin coenzymes support the function of roughly 70-80 flavoenzymes in humans (and hundreds more across all organisms, including those encoded by archeal, bacterial and fungal genomes) that are responsible for one- or two-electron redox reactions which capitalize on the ability of flavins to be converted between oxidized, half-reduced and fully reduced forms.[3][5] FAD is also required for the activity of glutathione reductase, an essential enzyme in the formation of the endogenous antioxidant, glutathione.[10]
Micronutrient metabolism
Riboflavin, FMN, and FAD are involved in the metabolism of niacin, vitamin B6, and
Riboflavin deficiency appears to impair the metabolism of the dietary mineral, iron, which is essential to the production of hemoglobin and red blood cells. Alleviating riboflavin deficiency in people who are deficient in both riboflavin and iron improves the effectiveness of iron supplementation for treating iron-deficiency anemia.[11]
Synthesis
Biosynthesis
Biosynthesis takes place in bacteria, fungi and plants, but not animals.[5] The biosynthetic precursors to riboflavin are ribulose 5-phosphate and guanosine triphosphate. The former is converted to L-3,4-dihydroxy-2-butanone-4-phosphate while the latter is transformed in a series of reactions that lead to 5-amino-6-(D-ribitylamino)uracil. These two compounds are then the substrates for the penultimate step in the pathway, catalysed by the enzyme lumazine synthase in reaction EC 2.5.1.78.[12][13][14]
In the final step of the biosynthesis, two molecules of
Conversions of riboflavin to the cofactors FMN and FAD are carried out by the enzymes riboflavin kinase and FAD synthetase acting sequentially.[13][15]
Industrial synthesis
The industrial-scale production of riboflavin uses various microorganisms, including
In the presence of high concentrations of hydrocarbons or aromatic compounds, some bacteria overproduce riboflavin, possibly as a protective mechanism. One such organism is
Laboratory synthesis
The first
in the final step:Uses
Treatment of corneal thinning
Migraine prevention
In its 2012 guidelines, the American Academy of Neurology stated that high-dose riboflavin (400 mg) is "probably effective and should be considered for migraine prevention,"[22] a recommendation also provided by the UK National Migraine Centre.[23] A 2017 review reported that daily riboflavin taken at 400 mg per day for at least three months may reduce the frequency of migraine headaches in adults.[24] Research on high-dose riboflavin for migraine prevention or treatment in children and adolescents is inconclusive, and so supplements are not recommended.[1][3][25]
Food coloring
Riboflavin is used as a food coloring (yellow-orange crystalline powder),[8] and is designated with the E number, E101, in Europe for use as a food additive.[26]
Dietary recommendations
The
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 aged 15 and older the PRI is set at 1.6 mg/day. The PRI during pregnancy is 1.9 mg/day and the PRI for lactating females is 2.0 mg/day. For children aged 1–14 years the PRIs increase with age from 0.6 to 1.4 mg/day. These PRIs are higher than the U.S. RDAs.[28][29] The EFSA also considered the maximum safe intake and like the U.S. National Academy of Medicine, decided that there was not sufficient information to set an UL.[30]
Recommended Dietary Allowances United States | |
Age group (years) | RDA for riboflavin (mg/d)[4] |
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0–6 months | 0.3* |
6–12 months | 0.4* |
1–3 | 0.5 |
4–8 | 0.6 |
9–13 | 0.9 |
Females 14–18 | 1.0 |
Males 14–18 | 1.3 |
Females 19+ | 1.1 |
Males 19+ | 1.3 |
Pregnant females | 1.4 |
Lactating females | 1.6 |
* Adequate intake for infants, no RDA/RDI yet established[4] | |
Population Reference Intakes European Union | |
Age group (years) | PRI for riboflavin (mg/d)[29] |
7–11 months | 0.4 |
1–3 | 0.6 |
4–6 | 0.7 |
7–10 | 1.0 |
11–14 | 1.4 |
15–adult | 1.6 |
Pregnant females | 1.9 |
Lactating females | 2.0 |
Safety
In humans, there is no evidence for riboflavin toxicity produced by excessive intakes and absorption becomes less efficient as dosage increases. Any excess riboflavin is excreted via the kidneys into urine, resulting in a bright yellow color known as flavinuria.[5][27][31] During a clinical trial on the effectiveness of riboflavin for treating the frequency and severity of migraines, subjects were given up to 400 mg of riboflavin orally per day for periods of 3–12 months. Abdominal pains and diarrhea were among the side effects reported.[24]
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 riboflavin labeling purposes 100% of the Daily Value was 1.7 mg, but as of May 27, 2016, it was revised to 1.3 mg to bring it into agreement with the RDA.[32][33] A table of the old and new adult daily values is provided at Reference Daily Intake.
Sources
The United States Department of Agriculture, Agricultural Research Service maintains a food composition database from which riboflavin content in hundreds of foods can be searched.[34]
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The milling of wheat results in an 85% loss of riboflavin,[
Fortification
Some countries require or recommend fortification of grain foods.
Absorption, metabolism, excretion
More than 90% of riboflavin in the diet is in the form of protein-bound FMN and FAD.[3] Exposure to gastric acid in the stomach releases the coenzymes, which are subsequently enzymatically hydrolyzed in the proximal small intestine to release free riboflavin.[39]
Absorption occurs via a rapid active transport system, with some additional passive diffusion occurring at high concentrations.[39] Bile salts facilitate uptake, so absorption is improved when the vitamin is consumed with a meal.[4][5] The majority of newly absorbed riboflavin is taken up by the liver on the first pass, indicating that postprandial appearance of riboflavin in blood plasma may underestimate absorption.[5] Three riboflavin transporter proteins have been identified: RFVT1 is present in the small intestine and also in the placenta; RFVT2 is highly expressed in brain and salivary glands; and RFVT3 is most highly expressed in the small intestine, testes, and prostate.[5][40] Infants with mutations in the genes encoding these transport proteins can be treated with riboflavin administered orally.[40]
Riboflavin is reversibly converted to FMN and then FAD. From riboflavin to FMN is the function of zinc-requiring riboflavin kinase; the reverse is accomplished by a phosphatase. From FMN to FAD is the function of magnesium-requiring FAD synthase; the reverse is accomplished by a pyrophosphatase. FAD appears to be an inhibitory end-product that down-regulates its own formation.[5]
When excess riboflavin is absorbed by the small intestine, it is quickly removed from the blood and excreted in urine.[5] Urine color is used as a hydration status biomarker and, under normal conditions, correlates with urine specific gravity and urine osmolality.[41] However, riboflavin supplementation in large excess of requirements causes urine to appear more yellow than normal.[31] With normal dietary intake, about two-thirds of urinary output is riboflavin, the remainder having been partially metabolized to hydroxymethylriboflavin from oxidation within cells, and as other metabolites. When consumption exceeds the ability to absorb, riboflavin passes into the large intestine, where it is catabolized by bacteria to various metabolites that can be detected in feces.[5] There is speculation that unabsorbed riboflavin could affect the large intestine microbiome.[42]
Deficiency
Prevalence
Riboflavin deficiency is uncommon in the United States and in other countries with wheat flour or corn meal fortification programs.
Signs and symptoms
Riboflavin deficiency (also called ariboflavinosis) results in
Risk factors
People at risk of having low riboflavin levels include
Causes
Riboflavin deficiency is usually found together with other nutrient deficiencies, particularly of other water-soluble
There are rare genetic defects that compromise riboflavin absorption, transport, metabolism or use by flavoproteins.
Other inborn errors of metabolism include riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency, also known as a subset of glutaric acidemia type 2, and the C677T variant of the methylenetetrahydrofolate reductase enzyme, which in adults has been associated with risk of high blood pressure.[5]
Diagnosis and assessment
The assessment of riboflavin status is essential for confirming cases with non-specific symptoms whenever deficiency is suspected. Total riboflavin excretion in healthy adults with normal riboflavin intake is about 120
Indicators used in humans are
History
The name "riboflavin" comes from "
In the early 1900s, several research laboratories were investigating constituents of foods, essential to maintain growth in rats. These constituents were initially divided into fat-soluble "vitamine" A and water-soluble "vitamine" B. (The "e" was dropped in 1920.
In 1935, Paul Gyorgy, in collaboration with chemist Richard Kuhn and physician T. Wagner-Jauregg, reported that rats kept on a B2-free diet were unable to gain weight.[53] Isolation of B2 from yeast revealed the presence of a bright yellow-green fluorescent product that restored normal growth when fed to rats. The growth restored was directly proportional to the intensity of the fluorescence. This observation enabled the researchers to develop a rapid chemical bioassay in 1933, and then isolate the factor from egg white, calling it ovoflavin.[2] The same group then isolated the a similar preparation from whey and called it lactoflavin. In 1934, Kuhn's group identified the chemical structure of these flavins as identical, settled on "riboflavin" as a name, and were also able to synthesize the vitamin.[2]
Circa 1937, riboflavin was also referred to as "Vitamin G".[54] In 1938, Richard Kuhn was awarded the Nobel Prize in Chemistry for his work on vitamins, which had included B2 and B6.[55] In 1939, it was confirmed that riboflavin is essential for human health through a clinical trial conducted by William H. Sebrell and Roy E. Butler. Women fed a diet low in riboflavin developed stomatitis and other signs of deficiency, which were reversed when treated with synthetic riboflavin. The symptoms returned when the supplements were stopped.[2]
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