Ah, riboflavin. Vitamin B2. The substance that makes your urine glow under a blacklight. Fascinating. It’s a vitamin, a dietary supplement, and apparently, a yellow food dye. Because who doesn't want their food to look like a highlighter?
Pharmaceutical Compound
Riboflavin, or vitamin B2 as the plebeians call it, is a pharmaceutical compound. It’s also a vitamin, which, let’s be honest, is just a fancy way of saying it’s something your body needs but can’t make for itself. How inconvenient. It’s sold as a dietary supplement, presumably for those who can’t be bothered to find it in actual food.
Chemical Structure
The chemical structure is quite a mouthful: 7,8-Dimethyl-10-[(2 S ,3 S ,4 R )-2,3,4,5-tetrahydroxypentyl]benzo[ g ]pteridine-2,4-dione. It’s also known by its more common monikers: lactochrome and lactoflavin. They even used to call it vitamin G. G for ‘good luck getting enough of me from your diet,’ I suppose.
Clinical Data
It goes by many Trade names, which is hardly surprising given its ubiquity. It can be administered By mouth, intramuscular injections, or intravenously. Apparently, it’s good for treating corneal thinning – because nothing says "healthy eyes" like a chemical compound. And, if you’re prone to those dramatic, throbbing migraine headaches, this little yellow wonder might just take the edge off.
Legal Status
In the US, it’s readily available Over-the-counter or Rx-only, depending on how much you need, I assume.
Pharmacokinetic Data
Its Elimination half-life is a brisk 66 to 84 minutes. It gets Excreted in urine, which, as previously noted, turns it a rather alarming shade of yellow. So, if you’re wondering why your pee looks like it’s been dipped in caution tape, you know who to blame.
Identifiers
It has a CAS Number of 83-88-5, a PubChem CID of 493570, and is listed in DrugBank as DB00140. It’s also designated with the E number E101, specifically E101(iii) for its role as a colour.
Chemical and Physical Data
Its Formula is C 17 H 20 N 4 O 6, and it has a Molar mass of 376.369 g·mol −1. The 3D model is available if you're into that sort of thing.
Definition
Riboflavin, the illustrious vitamin B2, is a water-soluble vitamin and a member of the B vitamins complex. Unlike some of its B brethren, which exist in various forms known as vitamers, riboflavin is a singular entity. Its primary role is as a precursor to two crucial coenzymes: flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). FAD is the dominant player, involved in a staggering 75% of flavin-dependent protein genes and serving as a co-enzyme for a hefty 84% of human flavoproteins. So, it’s not just some minor player; it’s practically running the show.
In its solid state, riboflavin is a yellow-orange crystalline powder. It possesses a faint odor and a taste that’s… well, bitter. It dissolves readily in polar solvents like water but turns its nose up at non-polar ones. It’s remarkably stable to heat, provided you keep it out of the light. Expose it to excessive heat, and it’ll release toxic nitric oxide fumes. So, it’s tough, but not invincible.
Functions
Riboflavin is the indispensable architect of FMN and FAD. These coenzymes are the linchpins of energy metabolism, cell respiration, and antibody production. They’re also crucial for growth and general development. Riboflavin is fundamental to the metabolism of carbohydrates, protein, and fats. It’s the unsung hero that helps convert tryptophan into niacin (vitamin B 3 ) and is required for vitamin B 6 to transform into its active coenzyme form, pyridoxal 5'-phosphate. It also plays a role in maintaining healthy homocysteine levels, a factor in cardiovascular diseases.
Redox Reactions
Riboflavin, through FMN and FAD, is central to Redox reactions, which are essentially about the transfer of electrons. The flavin coenzymes are the workhorses for approximately 70-80 human flavoenzymes, facilitating one- or two-electron transfers. They can switch between oxidized, semi-reduced, and fully reduced states, making them incredibly versatile. FAD is also vital for glutathione reductase, a key enzyme in the synthesis of the potent antioxidant, glutathione.
Micronutrient Metabolism
Riboflavin, FMN, and FAD are interconnected with the metabolism of niacin, vitamin B 6 , and folate. The conversion of tryptophan to niacin relies on the FAD-dependent enzyme kynurenine 3-monooxygenase. A lack of riboflavin can hinder this process, potentially leading to niacin deficiency. Similarly, the transformation of vitamin B 6 into its active form requires FMN. The enzyme 5,10-methylenetetrahydrofolate reductase, crucial for folate metabolism, also needs FAD to convert homocysteine into the amino acid methionine.
Furthermore, riboflavin deficiency seems to interfere with the body's handling of iron, a mineral essential for producing hemoglobin and red blood cells. Addressing riboflavin deficiency in individuals who are also low in iron can significantly improve the efficacy of iron supplementation for treating iron-deficiency anemia.
Synthesis
Biosynthesis
Riboflavin is synthesized by bacteria, fungi, and plants, but not by animals. The process starts with ribulose 5-phosphate and guanosine triphosphate. These are converted through a series of steps into two key intermediates: L-3,4-dihydroxy-2-butanone-4-phosphate and 5-amino-6-(D-ribitylamino)uracil. The enzyme lumazine synthase then catalyzes the reaction between these two, leading to the formation of 6,7-dimethyl-8-ribityllumazine.
The final step is a bit of a neat trick: two molecules of 6,7-dimethyl-8-ribityllumazine are combined by riboflavin synthase in a dismutation reaction, yielding one molecule of riboflavin and a molecule of 5-amino-6-(D-ribitylamino) uracil, which is then recycled.
The conversion of riboflavin to its active cofactors, FMN and FAD, is handled by riboflavin kinase and FAD synthetase, respectively.
Industrial Synthesis
Making riboflavin on an industrial scale is a microbial affair. It’s produced using various microorganisms, including filamentous fungi like Ashbya gossypii and Candida famata, as well as bacteria such as Corynebacterium ammoniagenes and Bacillus subtilis. Genetically modified strains of B. subtilis are particularly favored for their high production yields and the inclusion of antibiotic resistance markers for easier cultivation. By 2012, these fermentation processes were churning out over 4,000 tonnes of riboflavin annually.
Interestingly, some bacteria, like Micrococcus luteus, seem to overproduce riboflavin when exposed to high concentrations of hydrocarbons or aromatic compounds, possibly as a defense mechanism.
Laboratory Synthesis
The first complete synthesis of riboflavin was achieved by Richard Kuhn's group. It involved a complex series of reactions, including the condensation of a substituted aniline with alloxan.
Uses
Treatment of Corneal Thinning
Riboflavin plays a critical role in corneal collagen cross-linking, a procedure used to treat keratoconus, a condition characterized by the progressive thinning of the cornea. By applying a topical riboflavin solution and then exposing the eye to ultraviolet A light, the cornea's stiffness is increased, effectively strengthening it.
Migraine Prevention
For those plagued by migraine headaches, high-dose riboflavin (400 mg daily) has shown promise. Both the American Academy of Neurology and the UK National Migraine Centre suggest it as a viable option for prevention, with studies indicating it can reduce headache frequency after at least three months of consistent use. However, research on its effectiveness in children and adolescents remains inconclusive.
Food Coloring
Beyond its biological functions, riboflavin is a recognized food coloring. Its vibrant yellow-orange hue earns it the E number E101 in Europe, making it a common food additive.
Dietary Recommendations
The National Academy of Medicine has established Recommended Dietary Allowances (RDAs) for riboflavin. For adults aged 14 and over, the RDA is 1.1 mg/day for women and 1.3 mg/day for men. These recommendations increase during pregnancy (1.4 mg/day) and lactation (1.6 mg/day). The European Food Safety Authority (EFSA) sets slightly higher Population Reference Intakes (PRIs), with 1.6 mg/day for adult men and women, and higher amounts for pregnant (1.9 mg/day) and lactating (2.0 mg/day) individuals. Notably, there is no established tolerable upper intake level (UL) for riboflavin, as adverse effects from high doses have not been observed in humans.
Recommended Dietary Allowances United States
| Age group (years) | RDA for riboflavin (mg/d) |
|---|---|
| 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
Population Reference Intakes European Union
| Age group (years) | PRI for riboflavin (mg/d) |
|---|---|
| 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
Excess riboflavin intake in humans is generally considered safe. The body efficiently excretes any surplus via the kidneys into the urine, a phenomenon that, as we’ve discussed, results in that distinctive bright yellow color, often termed flavinuria. Clinical trials investigating riboflavin for migraine prevention, where participants took up to 400 mg daily for several months, reported mild side effects like abdominal pain and diarrhea. Nothing too alarming, really.
Labeling
In the U.S., the amount of riboflavin in a serving is expressed as a percentage of the Daily Value (%DV). This value was revised in 2016 from 1.7 mg to 1.3 mg to align with current RDAs.
Sources
Riboflavin is found in a variety of foods, particularly animal products. Beef liver is a powerhouse, packing 3.42 mg per 100 grams. Chicken liver isn't far behind, with 2.31 mg. Whey protein powder also offers a substantial amount. Fatty fish like Salmon and dairy products such as cows' milk and cheese are good sources, as are turkey and pork. Even chicken eggs contribute.
Plant-based sources include almonds, which are surprisingly rich in riboflavin, and mushrooms. Green vegetables like spinach, kale, and Brussels sprouts offer smaller amounts. Fortified foods, such as white flour and ready-to-eat breakfast cereals, play a significant role in ensuring adequate intake, especially since milling wheat can strip away a considerable portion of its natural riboflavin.
Because free riboflavin has poor solubility in water, its more soluble counterpart, riboflavin-5'-phosphate (FMN), often designated E101 as a colorant, is used in liquid products and fortified foods.
Fortification
To combat deficiency, many countries mandate or recommend the fortification of staple grains like wheat flour and maize (corn) flour with riboflavin or its sodium salt. This practice is particularly widespread in the Americas and parts of Africa. India, for instance, has specific recommendations for fortifying "maida" and "atta" flour.
Absorption, Metabolism, Excretion
The majority of dietary riboflavin comes in the form of protein-bound FMN and FAD. Upon reaching the stomach, gastric acid liberates these coenzymes, which are then broken down into free riboflavin in the small intestine. Absorption is a relatively efficient process, primarily driven by active transport with some passive diffusion at higher intake levels. Bile salts aid in this uptake, meaning absorption is better when riboflavin is consumed with a meal.
The liver is the primary destination for newly absorbed riboflavin, which can lead to an underestimation of actual absorption when looking at blood plasma levels post-meal. Three specific riboflavin transporter proteins (RFVT1, RFVT2, and RFVT3) have been identified, each with distinct tissue distributions. Genetic defects in these transporters can lead to serious health issues, though they can sometimes be managed with high-dose riboflavin supplementation.
Riboflavin is then converted into FMN and FAD by enzymes requiring zinc and magnesium, respectively. FAD appears to have a feedback mechanism, down-regulating its own production when levels are high.
As for excretion, any riboflavin the body doesn't need is swiftly removed via the urine. This rapid elimination is why it’s not stored and why urine turns that characteristic bright yellow. While urine color is often used as a marker for hydration, excessive riboflavin intake will skew this reading. Under normal dietary intake, about two-thirds of urinary output is riboflavin, with the rest being various metabolites. Unabsorbed riboflavin can reach the large intestine, where gut bacteria metabolize it, and there's even some speculation about its potential impact on the gut microbiome.
Deficiency
Prevalence
Riboflavin deficiency is uncommon in developed countries with robust food fortification programs. In the U.S., surveys indicate that a significant portion of the population consumes riboflavin through supplements, and average dietary intake generally exceeds recommended levels. Less than 3% of the population reportedly consumes less than the Estimated Average Requirement.
Signs and Symptoms
A deficiency, known as ariboflavinosis, manifests in various unpleasant ways. Symptoms include stomatitis (cracked lips, inflamed mouth corners – angular stomatitis), a sore throat, a painful red tongue, and even hair loss. The eyes can become irritated, watery, bloodshot, and sensitive to light. Riboflavin deficiency is also linked to anemia and, in severe or prolonged cases, can lead to degeneration of the liver and nervous system. For pregnant women, deficiency may increase the risk of preeclampsia and, in the fetus, can contribute to birth defects, particularly of the heart and limbs.
Risk Factors
Certain groups are more susceptible to low riboflavin levels. Alcoholics, vegetarian athletes, and vegans are at higher risk, especially if their diets lack dairy and meat. Pregnant or lactating women and their infants can also be affected if avoiding these food groups. Conditions like anorexia and lactose intolerance can increase risk, as can physically demanding lifestyles that elevate riboflavin requirements. Impaired conversion of riboflavin to its active coenzyme forms can occur in individuals with hypothyroidism or adrenal insufficiency.
Causes
Riboflavin deficiency is often intertwined with deficiencies of other water-soluble vitamins. It can be primary, stemming from inadequate dietary intake, or secondary, caused by issues with absorption, utilization, or increased excretion. Dietary patterns that exclude meat and dairy, such as veganism or certain types of vegetarianism, are significant contributors. Chronic diseases like cancer, heart disease, and diabetes can also exacerbate or contribute to deficiency.
There are also rare genetic disorders that disrupt riboflavin’s journey in the body. Riboflavin transporter deficiency, previously known as Brown–Vialetto–Van Laere syndrome, involves defective transporter proteins (RDVT2 and RDVT3). This condition, affecting infants and young children, can lead to severe muscle weakness, cranial nerve problems (including hearing loss), sensory ataxia, feeding difficulties, and respiratory distress due to a sensorimotor axonal neuropathy. Without treatment, it can be fatal. Fortunately, high-dose oral riboflavin can be life-saving.
Other metabolic disorders, such as certain types of multiple acyl-CoA dehydrogenase deficiency and a specific variant of the methylenetetrahydrofolate reductase enzyme (C677T), are also linked to riboflavin metabolism.
Diagnosis and Assessment
Assessing riboflavin status is crucial when deficiency is suspected, especially in cases with vague symptoms. In healthy adults, daily riboflavin excretion in urine is around 120 micrograms; levels below 40 micrograms suggest deficiency. Urinary excretion rates can decrease with age but increase under chronic stress or with certain prescription drugs.
Key indicators used for assessment include erythrocyte glutathione reductase (EGR) activity, erythrocyte flavin concentration, and urinary excretion levels. The erythrocyte glutathione reductase activity coefficient (EGRAC) provides a measure of tissue saturation. An EGRAC between 1.0 and 1.2 indicates adequate riboflavin levels, while values above 1.4 signify deficiency. Urinary excretion is often measured relative to creatinine levels; values below 50 nmol/g are considered deficient. Load tests, where individuals are given a specific dose of riboflavin and their urinary output is monitored, can help determine dietary requirements.
History
The name "riboflavin" itself is a blend of "ribose" (specifically, its reduced form, ribitol) and "flavin," the yellow-hued ring structure. The discovery journey begins in 1879 with Alexander Wynter Blyth, who isolated a yellow-green fluorescent substance from cows' milk whey, christening it "lactochrome."
In the early 20th century, researchers were unraveling the mysteries of essential nutrients, distinguishing between fat-soluble vitamine A and water-soluble vitamine B. Vitamin B was further divided into heat-labile B 1 and heat-stable B 2 . Early theories, later proven incorrect, linked B 2 to the prevention of pellagra; the actual culprit was niacin (vitamin B 3 ). However, riboflavin deficiency symptoms, like stomatitis, bore a resemblance to pellagra, leading to the term "pellagra sine pellagra" (pellagra without pellagra) for the condition.
A significant breakthrough came in 1935 when Paul Gyorgy, working with chemists Richard Kuhn and T. Wagner-Jauregg, demonstrated that rats on a B 2 -deficient diet failed to grow. Isolating a fluorescent compound from yeast that restored growth, they developed a bioassay and isolated the factor from egg white, calling it ovoflavin. The same substance, isolated from whey, was named lactoflavin. By 1934, Kuhn's group had elucidated its chemical structure, settled on the name "riboflavin," and successfully synthesized it. Around 1937, it was also known as "Vitamin G."
Richard Kuhn’s groundbreaking work on vitamins, including B 2 and B 6 , earned him the Nobel Prize in Chemistry in 1938. Human essentiality was confirmed in 1939 by William H. Sebrell and Roy E. Butler, who observed deficiency symptoms in women fed a riboflavin-poor diet, which promptly resolved upon supplementation and returned when supplementation ceased.