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Chemical structure
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| Clinical data | |
|---|---|
| Trade names | many |
| Synonyms | vactochrome, lactoflavin, vitamin G |
| AHFS/Drugs.com | Monograph |
| Pregnancy category |
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| Routes of administration | by mouth, IM, IV |
| ATC code | |
| Legal status | |
| Legal status |
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| Pharmacokinetic data | |
| Excretion | Urine |
| Identifiers | |
| CAS Number | |
| PubChem CID | |
| IUPHAR/BPS | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEBI | |
| ChEMBL | |
| E number | E101 (colours)  |
| CompTox Dashboard (EPA) | |
| ECHA InfoCard | 100.001.370 |
| Chemical and physical data | |
| Formula | C17H20N4O6 |
| Molar mass | 376.369 g·mol−1 |
Riboflavin, also known as vitamin B2, is a vitamin found in food and used as a dietary supplement. Food sources include eggs, green vegetables, milk and other dairy product, meat, mushrooms, and almonds. Some countries require its addition to grains. As a supplement it is used to prevent and treat riboflavin deficiency and prevent migraines. It may be given by mouth or injection.
It is nearly always well tolerated. Normal doses are safe during pregnancy. Riboflavin is in the vitamin B group. It is required by the body for cellular respiration.
Riboflavin was discovered in 1920, isolated in 1933, and first made in 1935. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. Riboflavin is available as a generic medication and over the counter. In the United States a month of supplements costs less than 25 USD.
Medical uses
A solution of riboflavin.
Corneal ectasia
is a progressive thinning of the cornea; the most common form of this
condition is keratoconus. Collagen cross-linking by applying riboflavin
topically then shining UV light is a method to slow progression of
corneal ectasia by strengthening corneal tissue.
As of 2017 a system is marketed by Terumo
in Europe that is used to remove pathogens from blood; donated blood is
treated with riboflavin and then with ultraviolet light.
A 2017 review found that riboflavin may be useful to prevent
migraines in adults, but found that clinical trials in adolescents and
children had produced mixed outcomes.
Side effects
In
humans, there is no evidence for riboflavin toxicity produced by
excessive intakes, in part because it has lower water solubility than
other B vitamins, because absorption becomes less efficient as doses
increase, and because what exceeds the absorption is excreted via the
kidneys into urine.
Even when 400 mg of riboflavin per day was given orally to subjects in
one study for three months to investigate the efficacy of riboflavin in
the prevention of migraine headache, no short-term side effects were
reported. Although toxic doses can be administered by injection, any excess at nutritionally relevant doses is excreted in the urine,
imparting a bright yellow color when in large quantities. The limited
data available on riboflavin’s adverse effects do not mean, however,
that high intakes have no adverse effects, and the Food and Nutrition
Board urges people to be cautious about consuming excessive amounts of
riboflavin.
Function
Flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) function as cofactors for a variety of flavoprotein enzyme reactions:
- Flavoproteins of electron transport chain, including FMN in Complex I and FAD in Complex II
- FAD is required for the production of pyridoxic acid from pyridoxal (vitamin B6) by pyridoxine 5'-phosphate oxidase
- The primary coenzyme form of vitamin B6 (pyridoxal phosphate) is FMN dependent
- Oxidation of pyruvate, α-ketoglutarate, and branched-chain amino acids requires FAD in the shared E3 portion of their respective dehydrogenase complexes
- Fatty acyl CoA dehydrogenase requires FAD in fatty acid oxidation
- FAD is required to convert retinol (vitamin A) to retinoic acid via cytosolic retinal dehydrogenase
- Synthesis of an active form of folate (5-methyltetrahydrofolate) from 5,10-methylenetetrahydrofolate by Methylenetetrahydrofolate reductase is FADH2 dependent
- FAD is required to convert tryptophan to niacin (vitamin B3)
- Reduction of the oxidized form of glutathione (GSSG) to its reduced form (GSH) by Glutathione reductase is FAD dependent
Other Flavin derivatives such as N(5)-ethylflavinium ion, Et-Fl+, can oxidize water and produce O2.
Nutrition
Food sources
Food and beverages that provide riboflavin without fortification are milk, cheese, eggs, leaf vegetables, liver, kidneys, lean meats, legumes, mushrooms, and almonds.
The milling of cereals results in considerable loss (up to 60%) of vitamin B2, so white flour
is enriched in some countries by addition of the vitamin. The
enrichment of bread and ready-to-eat breakfast cereals contributes
significantly to the dietary supply of vitamin B2. Polished rice
is not usually enriched, because the vitamin’s yellow color would make
the rice visually unacceptable to the major rice-consuming populations.
However, most of the flavin content of whole brown rice is retained if
the rice is steamed (parboiled) prior to milling. This process drives
the flavins in the germ and aleurone layers into the endosperm. Free
riboflavin is naturally present in foods along with protein-bound FMN
and FAD. Bovine milk contains mainly free riboflavin, with a minor
contribution from FMN and FAD. In whole milk, 14% of the flavins are
bound noncovalently to specific proteins. Milk and yogurt contain some of the highest riboflavin content.
Egg white and egg yolk contain specialized riboflavin-binding proteins,
which are required for storage of free riboflavin in the egg for use by
the developing embryo.
Riboflavin is added to baby foods, breakfast cereals, pastas
and vitamin-enriched meal replacement products. It is difficult to
incorporate riboflavin into liquid products because it has poor
solubility in water, hence the requirement for riboflavin-5'-phosphate (E101a), a more soluble form of riboflavin. Riboflavin is also used as a food coloring and as such is designated in Europe as the E number E101.
Dietary recommendations
The National Academy of Medicine
(then the U.S. Institute of Medicine [IOM]) updated Estimated Average
Requirements (EARs) and Recommended Dietary Allowances (RDAs) for
riboflavin in 1998. The current EARs for riboflavin for women and men
ages 14 and up are 0.9 mg/day and 1.1 mg/day, respectively; the RDAs are
1.1 and 1.3 mg/day, respectively. RDAs are higher than EARs so as to
identify amounts that will cover people with higher than average
requirements. RDA for pregnancy is 1.4 mg/day. RDA for lactation is
1.6 mg/day. For infants up to 12 months the Adequate Intake (AI) is
0.3–0.4 mg/day. and for children ages 1–13 years the RDA increases with
age from 0.5 to 0.9 mg/day. As for safety, the IOM sets Tolerable upper intake levels
(ULs) for vitamins and minerals when evidence is sufficient. In the
case of riboflavin 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 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 defined the same as in
United States. For women and men ages 15 and older the PRI is set at
1.6 mg/day. PRI for pregnancy is 1.9 mg/day, for lactation 2.0 mg/day.
For children ages 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. The EFSA also reviewed the safety question and like the U.S., decided that there was not sufficient information to set an UL.
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. A table of the old and new adult Daily Values is provided at Reference Daily Intake.
The original deadline to be in compliance was July 28, 2018, but on
September 29, 2017 the FDA released a proposed rule that extended the
deadline to January 1, 2020 for large companies and January 1, 2021 for
small companies.
Deficiency
Signs and symptoms
Mild deficiencies can exceed 50% of the population in Third World
countries and in refugee situations. Deficiency is uncommon in the
United States and in other countries that have wheat flour, bread,
pasta, corn meal or rice enrichment regulations. In the U.S., starting
in the 1940s, flour, corn meal and rice have been fortified with B
vitamins as a means of restoring some of what is lost in milling,
bleaching and other processing. For adults 20 and older, average intake
from food and beverages is 1.8 mg/day for women and 2.5 mg/day for men.
An estimated 23% consume a riboflavin-containing dietary supplement that
provides on average 10 mg. The U.S. Department of Health and Human
Services conducts National Health and Nutrition Examination Survey every
two years and reports food results in a series of reports referred to
as "What We Eat In America." From NHANES 2011–2012, estimates were that
8% of women and 3% of men consumed less than the RDA. When compared to
the lower Estimated Average Requirements, fewer than 3% did not achieve
the EAR level.
Riboflavin deficiency (also called ariboflavinosis) results in stomatitis
including painful red tongue with sore throat, chapped and fissured
lips (cheilosis), and inflammation of the corners of the mouth (angular stomatitis). There can be oily scaly skin rashes on the scrotum, vulva, philtrum of the lip, or the nasolabial folds. The eyes can become itchy, watery, bloodshot and sensitive to light. Due to interference with iron absorption, even mild to moderate riboflavin deficiency results in an anemia with normal cell size and normal hemoglobin content (i.e. normochromic normocytic anemia). This is distinct from anemia caused by deficiency of folic acid (B9) or cyanocobalamin (B12), which causes anemia with large blood cells (megaloblastic anemia). Deficiency of riboflavin during pregnancy can result in birth defects including congenital heart defects and limb deformities. Prolonged riboflavin insufficiency is also known to cause degeneration of the liver and nervous system.
The stomatitis symptoms are similar to those seen in pellagra, which is caused by niacin (B3)
deficiency. Therefore, riboflavin deficiency is sometimes called
"pellagra sine pellagra" (pellagra without pellagra), because it causes
stomatitis but not widespread peripheral skin lesions characteristic of
niacin deficiency.
Riboflavin deficiency prolongs recovery from malaria, despite preventing growth of plasmodium (the malaria parasite).
Causes
Riboflavin is continuously excreted in the urine of healthy individuals, making deficiency relatively common when dietary intake is insufficient. Riboflavin deficiency is usually found together with other nutrient deficiencies, particularly of other water-soluble vitamins.
A deficiency of riboflavin can be primary – poor vitamin sources in
one's daily diet – or secondary, which may be a result of conditions
that affect absorption in the intestine, the body not being able to use
the vitamin, or an increase in the excretion of the vitamin from the
body.
Subclinical deficiency has also been observed in women taking oral
contraceptives, in the elderly, in people with eating disorders, chronic
alcoholism and in diseases such as HIV, inflammatory bowel disease,
diabetes and chronic heart disease. The Celiac Disease Foundation points
out that a gluten-free diet may be low in riboflavin (and other
nutrients) as enriched wheat flour and wheat foods (bread, pasta,
cereals, etc.) is a major dietary contribution to total riboflavin
intake.
Phototherapy to treat jaundice in infants can cause increased degradation of riboflavin, leading to deficiency if not monitored closely.
Diagnosis
Overt
clinical signs are rarely seen among inhabitants of the developed
countries. The assessment of riboflavin status is essential for
confirming cases with unspecific symptoms where deficiency is suspected.
- Glutathione reductase is a nicotinamide adenine dinucleotide phosphate (NADPH) and FAD-dependent enzyme, and the major flavoprotein in erythrocytes. The measurement of the activity coefficient of erythrocyte glutathione reductase (EGR) is the preferred method for assessing riboflavin status. It provides a measure of tissue saturation and long-term riboflavin status. In vitro enzyme activity in terms of activity coefficients (AC) is determined both with and without the addition of FAD to the medium. ACs represent a ratio of the enzyme’s activity with FAD to the enzyme’s activity without FAD. An AC of 1.2 to 1.4, riboflavin status is considered low when FAD is added to stimulate enzyme activity. An AC > 1.4 suggests riboflavin deficiency. On the other hand, if FAD is added and AC is < 1.2, then riboflavin status is considered acceptable. Tillotson and Bashor reported that a decrease in the intakes of riboflavin was associated with increase in EGR AC. In the UK study of Norwich elderly, initial EGR AC values for both males and females were significantly correlated with those measured 2 years later, suggesting that EGR AC may be a reliable measure of long-term biochemical riboflavin status of individuals. These findings are consistent with earlier studies.
- Experimental balance studies indicate that urinary riboflavin excretion rates increase slowly with increasing intakes, until intake level approach 1.0 mg/d, when tissue saturation occurs. At higher intakes, the rate of excretion increases dramatically. Once intakes of 2.5 mg/d are reached, excretion becomes approximately equal to the rate of absorption At such high intake a significant proportion of the riboflavin intake is not absorbed. If urinary riboflavin excretion is <19 40="" are="" creatinine="" day="" deficiency.="" g="" indicative="" intake="" nbsp="" of="" or="" per="" recent="" riboflavin="" span="" without="">
Treatment
Treatment involves a diet which includes an adequate amount of riboflavin containing foods.
Multi-vitamin and mineral dietary supplements often contain 100% of the
Daily Value (1.3 mg) for riboflavin, and can be used by persons
concerned about an inadequate diet. Over-the-counter dietary supplements
are available in the United States with doses as high as 100 mg, but
there is no evidence that these high doses have any additional benefit
for healthy people.
Other animals
In other animals, riboflavin deficiency results in lack of growth,
failure to thrive, and eventual death. Experimental riboflavin
deficiency in dogs results in growth failure, weakness, ataxia, and
inability to stand. The animals collapse, become comatose, and die.
During the deficiency state, dermatitis develops together with hair
loss. Other signs include corneal opacity, lenticular cataracts,
hemorrhagic adrenals, fatty degeneration of the kidney and liver, and
inflammation of the mucous membrane of the gastrointestinal tract.
Post-mortem studies in rhesus monkeys fed a riboflavin-deficient diet
revealed about one-third the normal amount of riboflavin was present in
the liver, which is the main storage organ for riboflavin in mammals. Riboflavin deficiency in birds results in low egg hatch rates.
Chemistry
As a
chemical compound, riboflavin is a yellow-orange solid substance with
poor solubility in water compared to other B vitamins. Visually, it
imparts color to vitamin supplements (and bright yellow color of urine
in persons taking it).
Industrial uses
Fluorescent spectra of riboflavin
A
solution of riboflavin in water (right) is yellow with chartreuse
fluorescence under fluorescent room lighting. The beaker prepared at
left holds a detergent in water, forming micelles that will show the passage of a visible laser beam.
A
473 nm 200 mW blue laser beam is directed into the two beakers from the
left. The detergent shows the path of the beam by blue scattered light.
The light from the riboflavin solution is intense green fluorescence
showing along the path of this laser beam.
Because riboflavin is fluorescent under UV light,
dilute solutions (0.015–0.025% w/w) are often used to detect leaks or
to demonstrate coverage in an industrial system such a chemical blend
tank or bioreactor. (See the ASME BPE section on Testing and Inspection for additional details.)
Industrial synthesis
Large cultures of Micrococcus luteus
growing on pyridine (left) and succinic acid (right). The yellow
pigment being produced in the presence of pyridine is riboflavin.
The industrial scale production of riboflavin using diverse microorganisms, including filamentous fungi such as Ashbya gossypii, Candida famata and Candida flaveri, as well as the bacteria Corynebacterium ammoniagenes and Bacillus subtilis. The latter organism, genetically modified to both increase the production of riboflavin and to introduce an antibiotic (ampicillin)
resistance marker, is employed at a commercial scale to produce
riboflavin for feed and food fortification. The chemical company BASF has installed a plant in South Korea, which is specialized on riboflavin production using Ashbya gossypii. The concentrations of riboflavin in their modified strain are so high that the mycelium has a reddish/brownish color and accumulates riboflavin crystals in the vacuoles,
which will eventually burst the mycelium. Riboflavin is sometimes
overproduced, possibly as a protective mechanism, by some bacteria in
the presence of high concentrations of hydrocarbons or aromatic
compounds. One such organism is Micrococcus luteus (American Type Culture Collection
strain number ATCC 49442), which develops a yellow color due to
production of riboflavin while growing on pyridine, but not when grown
on other substrates, such as succinic acid.
History
Vitamin B was originally considered to have two components, a heat-labile vitamin B1 and a heat-stable vitamin B2. In the 1920s, vitamin B2 was thought to be the factor necessary for preventing pellagra. In 1923, Paul Gyorgy in Heidelberg was investigating egg-white injury in rats; the curative factor for this condition was called vitamin H (which is now called biotin or vitamin B7). Since both pellagra and vitamin H deficiency were associated with dermatitis, Gyorgy decided to test the effect of vitamin B2 on vitamin H deficiency in rats. He enlisted the service of Wagner-Jauregg in Kuhn’s laboratory.
In 1933, Kuhn, Gyorgy, and Wagner found that thiamin-free extracts of
yeast, liver, or rice bran prevented the growth failure of rats fed a
thiamin-supplemented diet.
Further, the researchers noted that a yellow-green fluorescence
in each extract promoted rat growth, and that the intensity of
fluorescence was proportional to the effect on growth. This observation enabled them to develop a rapid chemical and bioassay to isolate the factor from egg white in 1933.
The same group then isolated the same preparation (a growth-promoting
compound with yellow-green fluorescence) from whey using the same
procedure (lactoflavin). In 1934, Kuhn’s group identified the structure
of so-called flavin and synthesized vitamin B2, leading to evidence in 1939 that riboflavin was essential for human health.
Etymology
The name "riboflavin" (often abbreviated to Rbf or RBF) comes from "ribose" (the sugar whose reduced form, ribitol, forms part of its structure) and "flavin", the ring-moiety which imparts the yellow color to the oxidized molecule (from Latin flavus, "yellow"). The reduced form, which occurs in metabolism along with the oxidized form, is colorless.
