Professional Documents
Culture Documents
Functions (https://dailymed.nlm.ni
Redox reactions h.gov/dailymed/search.
Micronutrient metabolism cfm?labeltype=all&quer
y=Riboflavin)
Synthesis
Biosynthesis Routes of By mouth,
administration
Industrial synthesis intramuscular,
Laboratory synthesis intravenous
Uses ATC code A11HA04 (WHO (http
Treatment of corneal thinning s://www.whocc.no/atc_
Migraine prevention ddd_index/?code=A11
Food coloring HA04)) S01XA26
(WHO (https://www.who
Dietary recommendations
Safety cc.no/atc_ddd_index/?c
ode=S01XA26))
Labeling
Sources Legal status
Fortification Legal status US: Dietary supplement
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 (https://enzyme.expasy.org/E
C/2.5.1.78).[12][13][14]
In the final step of the biosynthesis, two molecules of 6,7-dimethyl-8-ribityllumazine are combined by the
enzyme riboflavin synthase in a dismutation reaction. This generates one molecule of riboflavin and one of
5-amino-6-(D-ribitylamino) uracil. The latter is recycled to the previous reaction in the sequence.[12][13]
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 filamentous fungi such
as Ashbya gossypii, Candida famata and Candida flaveri, as well as the bacteria Corynebacterium
ammoniagenes and Bacillus subtilis. B. subtilis that has been 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.[17] By 2012, over 4,000
tonnes per annum were produced by such fermentation
processes.[18]
Laboratory synthesis
Keratoconus is the most common form of corneal ectasia, a progressive thinning of the cornea. The
condition is treated by corneal collagen cross-linking, which increases corneal stiffness. Cross-linking is
achieved by applying a topical riboflavin solution to the cornea, which is then exposed to ultraviolet A
light.[20][21]
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 National Academy of Medicine updated the Estimated Average Requirements (EARs) and
Recommended Dietary Allowances (RDAs) for riboflavin in 1998. The EARs for riboflavin for women
and men aged 14 and over 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 to provide adequate intake levels for individuals with higher than
average requirements. The RDA during pregnancy is 1.4 mg/day and the RDA for lactating females is
1.6 mg/day. For infants up to the age of 12 months, the Adequate Intake (AI) is 0.3–0.4 mg/day and for
children aged 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).[4][27]
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]
Safety
In humans, there is no evidence for riboflavin
toxicity produced by excessive intakes and Recommended Dietary Allowances United States
absorption becomes less efficient as doses RDA for riboflavin
Age group (years)
increases. Any excess riboflavin is excreted (mg/d)[4]
via the kidneys into urine, resulting in a 0–6 months 0.3*
bright yellow color known as
flavinuria. [5][27][31] During a clinical trial on 6–12 months 0.4*
the effectiveness of riboflavin for treating the 1–3 0.5
frequency and severity of migraines, subjects 4–8 0.6
were given up to 400 mg of riboflavin orally
per day for periods of 3–12 months. 9–13 0.9
Abdominal pains and diarrhea were among Females 14–18 1.0
the side effects reported.[24]
Males 14–18 1.3
7–10 1.0
The United States Department of Agriculture, 11–14 1.4
Agricultural Research Service maintains a
15–adult 1.6
food composition database from which
riboflavin content in hundreds of foods can Pregnant females 1.9
be searched.[34] Lactating females 2.0
The milling of wheat results in an 85% loss of riboflavin, so white flour is enriched in some countries.
Riboflavin is also added to baby foods, breakfast cereals, pastas and vitamin-enriched meal replacement
products.[3] It is difficult to incorporate riboflavin into liquid products because it has poor solubility in water,
hence the requirement for riboflavin-5'-phosphate (FMN, also called E101 when used as colorant), a more
soluble form of riboflavin.[26] The enrichment of bread and ready-to-eat breakfast cereals contributes
significantly to the dietary supply of the vitamin. Free riboflavin is naturally present in animal-sourced foods
along with protein-bound FMN and FAD. Cows' milk contains mainly free riboflavin, but both FMN and
FAD are present at low concentrations.[35]
Fortification
Some countries require or recommend fortification of grain foods.[36] As of 2021, 56 countries, mostly in
North and South America and southeast Africa, require food fortification of wheat flour or maize (corn)
flour with riboflavin or riboflavin-5'-phosphate sodium. The amounts stipulated range from 1.3 to
5.75 mg/kg.[37] An additional 16 countries have a voluntary fortification program. For example, the Indian
government recommends 4.0 mg/kg for "maida" (white) and "atta" (whole wheat) flour.[38]
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] One small clinical trial in adults reported that the maximum amount of riboflavin that can
be absorbed from a single dose is 27 mg.[39] 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.[37] From data collected in biannual surveys of the U.S. population, for ages 20
and over, 22% of females and 19% of men reported consuming a supplement that contained riboflavin,
typically a vitamin-mineral multi-supplement. For the non-supplement users, the dietary intake of adult
women averaged 1.74 mg/day and men 2.44 mg/day. These amounts exceed the RDAs for riboflavin of 1.1
and 1.3 mg/day respectively.[43] For all age groups, on average, consumption from food exceeded the
RDAs.[44] A 2001-02 U.S. survey reported that less than 3% of the population consumed less than the
Estimated Average Requirement of riboflavin.[45]
Riboflavin deficiency (also called ariboflavinosis) results in stomatitis, symptoms of which include chapped
and fissured lips, inflammation of the corners of the mouth (angular stomatitis), sore throat, painful red
tongue, and hair loss.[3] The eyes can become itchy, watery, bloodshot, and sensitive to light.[3] Riboflavin
deficiency is associated with anemia.[46] Prolonged riboflavin insufficiency may cause degeneration of the
liver and nervous system.[3][4] Riboflavin deficiency may increase the risk of preeclampsia in pregnant
women.[3][10] Deficiency of riboflavin during pregnancy can result in fetal birth defects, including heart and
limb deformities.[47][48]
Risk factors
People at risk of having low riboflavin levels include alcoholics, vegetarian athletes, and practitioners of
veganism.[3] Pregnant or lactating women and their infants may also be at risk, if the mother avoids meat
and dairy products.[3][10] Anorexia and lactose intolerance increase the risk of riboflavin deficiency.[10]
People with physically demanding lives, such as athletes and laborers, may require higher riboflavin
intake.[10] The conversion of riboflavin into FAD and FMN is impaired in people with hypothyroidism,
adrenal insufficiency, and riboflavin transporter deficiency.[10]
Causes
Riboflavin deficiency is usually found together with other nutrient deficiencies, particularly of other water-
soluble vitamins.[3] A deficiency of riboflavin can be primary (i.e. caused by poor vitamin sources in the
regular diet) or secondary, which may be a result of conditions that affect absorption in the intestine.
Secondary deficiencies are typically caused by the body not being able to use the vitamin, or by an
increased rate of excretion of the vitamin.[10] Diet patterns that increase risk of deficiency include veganism
and low-dairy vegetarianism.[5] Diseases such as cancer, heart disease and diabetes may cause or exacerbate
riboflavin deficiency.[4]
There are rare genetic defects that compromise riboflavin absorption, transport, metabolism or use by
flavoproteins.[40][49] One of these is riboflavin transporter deficiency, previously known as Brown-Vialetto-
Van Laere syndrome.[40][49] Variants of the genes SLC52A2 and SLC52A3 which code for transporter
proteins RDVT2 and RDVT3, respectively, are defective.[40][49] Infants and young children present with
muscle weakness, cranial nerve deficits including hearing loss, sensory symptoms including sensory ataxia,
feeding difficulties, and respiratory distress caused by a sensorimotor axonal neuropathy and cranial nerve
pathology.[49] When untreated, infants with riboflavin transporter deficiency have labored breathing and are
at risk of dying in the first decade of life. Treatment with oral supplementation of high amounts of riboflavin
is lifesaving.[40][49]
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 micrograms per day, while excretion of less than 40 micrograms per day indicates deficiency.[3][50]
Riboflavin excretion rates decrease as a person ages, but increase during periods of chronic stress and the
use of some prescription drugs.[3]
Indicators used in humans are erythrocyte glutathione reductase (EGR), erythrocyte flavin concentration
and urinary excretion.[4][5] The erythrocyte glutathione reductase activity coefficient (EGRAC) provides a
measure of tissue saturation and long-term riboflavin status.[50][3] Results are expressed as an activity
coefficient ratio, determined by enzyme activity with and without the addition of FAD to the culture
medium. An EGRAC of 1.0 to 1.2 indicates that adequate amounts of riboflavin are present; 1.2 to 1.4 is
considered low, greater than 1.4 indicates deficient.[3][5] For the less sensitive "erythrocyte flavin method",
values greater than 400 nmol/L are considered adequate and values below 270 nmol/L are considered
deficient.[4][50] Urinary excretion is expressed as nmol of riboflavin per gram of creatinine. Low is defined
as in the range of 50 to 72 nmol/g. Deficient is below 50 nmol/g. Urinary excretion load tests have been
used to determine dietary requirements. For adult men, as oral doses were increased from 0.5 mg to 1.1 mg,
there was a modest linear increase in urinary riboflavin, reaching 100 micrograms for a subsequent 24-hour
urine collection.[4] Beyond a load dose of 1.1 mg, urinary excretion increased rapidly, so that with a dose of
2.5 mg, urinary output was 800 micrograms for a 24-hour urine collection.[4]
History
The name "riboflavin" 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").[5] The reduced form, which occurs in metabolism along with the oxidized form, appears
as orange-yellow needles or crystals.[8] The earliest reported identification, predating any concept of
vitamins as essential nutrients, was by Alexander Wynter Blyth. In 1897, Blyth isolated a water-soluble
component of cows' milk whey, which he named "lactochrome", that fluoresced yellow-green when
exposed to light.[2]
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.[51]) Vitamin B was further thought to have two
components, a heat-labile substance called B1 and a heat-stable substance called B2 .[2] Vitamin B2 was
tentatively identified to be the factor necessary for preventing pellagra, but that was later confirmed to be
due to niacin (vitamin B3 ) deficiency. The confusion was due to the fact that riboflavin (B2 ) deficiency
causes stomatitis symptoms similar to those seen in pellagra, but without the widespread peripheral skin
lesions. For this reason, early in the history of identifying riboflavin deficiency in humans the condition was
sometimes called "pellagra sine pellagra" (pellagra without pellagra).[52]
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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