Riboflavin is a water-soluble B vitamin, also known as vitamin B2. In the body, riboflavin is primarily found as an integral component of the coenzymes, flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) (1). Coenzymes derived from riboflavin are termed flavocoenzymes, and enzymes that use a flavocoenzyme are called flavoproteins (2).
Oxidation-reduction (redox) reactions
Living organisms derive most of their energy from oxidation-reduction (redox) reactions, which are processes that involve the transfer of electrons. Flavocoenzymes participate in redox reactions in numerous metabolic pathways (3). Flavocoenzymes are critical for the metabolism of carbohydrates, fats, and proteins. FAD is part of the electron transport (respiratory) chain, which is central to energy production. In conjunction with cytochrome P-450, flavocoenzymes also participate in the metabolism of drugs and toxins (4).
Antioxidant functions
Glutathione reductase is a FAD-dependent enzyme that participates in the redox cycle of glutathione. The glutathione redox cycle plays a major role in protecting organisms from reactive oxygen species, such as hydroperoxides. Glutathione reductase requires FAD to regenerate two molecules of reduced glutathione from oxidized glutathione. Riboflavin deficiency has been associated with increased oxidative stress (4). Measurement of glutathione reductase activity in red blood cells is commonly used to assess riboflavin nutritional status (5).
Glutathione peroxidase, a selenium-containing enzyme, requires two molecules of reduced glutathione to break down hydroperoxides (see diagram).
Xanthine oxidase, another FAD-dependent enzyme, catalyzes the oxidation of hypoxanthine and xanthine to uric acid. Uric acid is one of the most effective water-soluble antioxidants in the blood. Riboflavin deficiency can result in decreased xanthine oxidase activity, reducing blood uric acid levels (6).
B-complex vitamins
Because flavoproteins are involved in the metabolism of several other vitamins (vitamin B6, niacin, and folic acid), severe riboflavin deficiency may affect many enzyme systems. Conversion of most naturally available vitamin B6 to its coenzyme form, pyridoxal 5'-phosphate (PLP), requires the FMN-dependent enzyme, pyridoxine 5'-phosphate oxidase (PPO) (7). At least two studies in the elderly have documented significant interactions between indicators of vitamin B6 and riboflavin nutritional status (8, 9). The synthesis of the niacin-containing coenzymes, NAD and NADP, from the amino acid, tryptophan, requires the FAD-dependent enzyme, kynurenine mono-oxygenase. Severe riboflavin deficiency can decrease the conversion of tryptophan to NAD and NADP, increasing the risk of niacin deficiency (3). Methylene tetrahydrofolate reductase (MTHFR) is a FAD-dependent enzyme that plays an important role in maintaining the specific folate coenzyme required to form methionine from homocysteine (see diagram). Along with other B vitamins, increased riboflavin intake has been associated with decreased plasma homocysteine levels (10). Recently, increased plasma riboflavin levels were associated with decreased plasma homocysteine levels, mainly in individuals homozygous for the C677T polymorphism of the MTHFR gene and in individuals with low folate intake (11). Such results illustrate that chronic disease risk may be influenced by complex interactions between genetic and dietary factors.
Iron
Riboflavin deficiency alters iron metabolism. Although the mechanism is not clear, research in animals suggests that riboflavin deficiency may impair iron absorption, increase intestinal loss of iron, and/or impair iron utilization for the synthesis of hemoglobin. In humans, improving riboflavin nutritional status has been found to increase circulating hemoglobin levels. Correction of riboflavin deficiency in individuals who are both riboflavin and iron deficient improves the response of iron-deficiency anemia to iron therapy (12).
Ariboflavinosis is the medical name for clinical riboflavin deficiency. Riboflavin deficiency is rarely found in isolation; it occurs frequently in combination with deficiencies of other water-soluble vitamins. Symptoms of riboflavin deficiency include sore throat, redness and swelling of the lining of the mouth and throat, cracks or sores on the outsides of the lips (cheliosis) and at the corners of the mouth (angular stomatitis), inflammation and redness of the tongue (magenta tongue), and a moist, scaly skin inflammation (seborrheic dermatitis). Other symptoms may involve the formation of blood vessels in the clear covering of the eye (vascularization of the cornea) and decreased red blood cell count in which the existing red blood cells contain normal levels of hemoglobin and are of normal size (normochromic normocytic anemia) (1, 3). Severe riboflavin deficiency may result in decreased conversion of vitamin B6 to its coenzyme form (PLP) and decreased conversion of tryptophan to niacin (see Nutrient Interactions).
Preeclampsia is defined as the presence of elevated blood pressure, protein in the urine, and edema (significant swelling) during pregnancy. About 5% of women with preeclampsia may progress to eclampsia, a significant cause of maternal death. Eclampsia is characterized by seizures, in addition to high blood pressure and increased risk of hemorrhage (severe bleeding) (13). A study in 154 pregnant women at increased risk of preeclampsia found that those who were riboflavin deficient were 4.7 times more likely to develop preeclampsia than those who had adequate riboflavin nutritional status. The cause of preeclampsia-eclampsia is not known. Decreased intracellular levels of flavocoenzymes could cause mitochondrial dysfunction, increase oxidative stress, and interfere with nitric oxide release and thus blood vessel dilation—all of these changes have been associated with preeclampsia (14). However, a small randomized, placebo-controlled, double-blind trial in 450 pregnant women with prior preeclampsia found that supplementation with 15 mg of riboflavin daily did not prevent the condition (15).
Risk factors for riboflavin deficiency
Alcoholics are at increased risk for riboflavin deficiency due to decreased intake, decreased absorption, and impaired utilization of riboflavin. Additionally, anorexic individuals rarely consume adequate riboflavin, and lactose intolerant individuals may not consume milk or other dairy products which are good sources of riboflavin. The conversion of riboflavin into FAD and FMN is impaired in hypothyroidism and adrenal insufficiency (3, 4). Further, people who are very active physically (athletes, laborers) may have a slightly increased riboflavin requirement. However, riboflavin supplementation has not generally been found to increase exercise tolerance or performance (16).
The Recommended Dietary Allowance (RDA)
The RDA for riboflavin, revised in 1998, was based on the prevention of deficiency. Clinical signs of deficiency in humans appear at intakes of less than 0.5-0.6 milligrams (mg)/day, and urinary excretion of riboflavin is seen at intake levels of approximately 1 mg/day (1).
| Recommended Dietary Allowance (RDA) for Riboflavin | |||
| Life Stage | Age | Males (mg/day) | Females (mg/day) |
| Infants | 0-6 months | 0.3 (AI) | 0.3 (AI) |
| Infants | 7-12 months | 0.4 (AI) | 0.4 (AI) |
| Children | 1-3 years | 0.5 | 0.5 |
| Children | 4-8 years | 0.6 | 0.6 |
| Children | 9-13 years | 0.9 | 0.9 |
| Adolescents | 14-18 years | 1.3 | 1.0 |
| Adults | 19 years and older | 1.3 | 1.1 |
| Pregnancy | all ages | - | 1.4 |
| Breast-feeding | all ages | - | 1.6 |
Age-related cataracts are the leading cause of visual disability in the U.S. and other developed countries. Research has focused on the role of nutritional antioxidants because of evidence that light-induced oxidative damage of lens proteins may lead to the development of age-related cataracts. A case-control study found significantly decreased risk of age-related cataract (33% to 51%) in men and women in the highest quintile of dietary riboflavin intake (median of 1.6 to 2.2 mg/day) compared to those in the lowest quintile (median of 0.08 mg/day in both men and women) (17). Another case-control study reported that individuals in the highest quintile of riboflavin nutritional status, as measured by red blood cell glutathione reductase activity, had approximately one half the occurrence of age-related cataract as those in the lowest quintile of riboflavin status, though the results were not statistically significant (18). A cross-sectional study of 2,900 Australian men and women, 49 years of age and older, found that those in the highest quintile of riboflavin intake were 50% less likely to have cataracts than those in the lowest quintile (19). A prospective study of more than 50,000 women did not observe a difference between rates of cataract extraction between women in the highest quintile of riboflavin intake (median of 1.5 mg/day) and women in the lowest quintile (median of 1.2 mg/day) (20). However, the range between the highest and lowest quintiles was small, and median intake levels for both quintiles were above the current RDA for riboflavin. A recent study in 408 women found that higher dietary intakes of riboflavin were inversely associated with five-year change in lens opacification (21). Although these observational studies provide support for the role of riboflavin in the prevention of cataracts, placebo-controlled intervention trials are needed to confirm the relationship.
Some evidence indicates that impaired mitochondrial oxygen metabolism in the brain may play a role in the pathology of migraine headaches. Because riboflavin is the precursor of the two flavocoenzymes (FAD and FMN) required by the flavoproteins of the mitochondrial electron transport chain, supplemental riboflavin has been investigated as a treatment for migraine. A randomized placebo-controlled trial examined the effect of 400 mg of riboflavin/day for three months on migraine prevention in 54 men and women with a history of recurrent migraine headaches (22). Riboflavin was significantly better than placebo in reducing attack frequency and the number of headache days, though the beneficial effect was most pronounced during the third month of treatment. A more recent study by the same investigators found that treatment with either a medication called a beta-blocker or high-dose riboflavin resulted in clinical improvement, but each therapy appeared to act on a distinct pathological mechanism: beta-blockers on abnormal cortical information processing and riboflavin on decreased brain mitochondrial energy reserve (23). A small study in 23 patients reported a reduction in median migraine attack frequency after supplementation with 400 mg of riboflavin daily for three months (24). However, a randomized, double-blind, placebo-controlled study that administered a combination of riboflavin (400 mg/day), magnesium, and feverfew to migraine sufferers reported no therapeutic benefit compared to those administered a placebo containing 25 mg/day of riboflavin (25). It should be noted that only about 25 mg of riboflavin can be absorbed in a single oral dose (26). Although these findings are preliminary, data from most studies to date suggest that riboflavin supplementation might be a useful adjunct to pharmacologic therapy in migraine prevention.
Food sources
Most plant and animal derived foods contain at least small quantities of riboflavin. In the U.S., wheat flour and bread have been enriched with riboflavin (as well as thiamin, niacin, and iron) since 1943. Data from large dietary surveys indicate that the average intake of riboflavin for men is about 2 mg/day and for women is about 1.5 mg/day; both intakes are well above the RDA. Intake levels were similar for a population of elderly men and women (1). Riboflavin is easily destroyed by exposure to light. For instance, up to 50% of the riboflavin in milk contained in a clear glass bottle can be destroyed after two hours of exposure to bright sunlight (6). Some foods with substantial amounts of riboflavin are listed in the table below along with their riboflavin content in milligrams (mg). For more information on the nutrient content of foods, search the USDA food composition database.
| Food | Serving | Riboflavin (mg) |
| Fortified cereal | 1 cup | 0.59 to 2.27 |
| Milk (nonfat) | 1 cup (8 ounces) | 0.34 |
| Cheddar cheese | 1 ounce | 0.11 |
| Egg (cooked) | 1 large | 0.27 |
| Almonds | 1 ounce | 0.23 |
| Salmon (cooked) | 3 ounces* | 0.12 |
| Halibut (broiled) | 3 ounces | 0.08 |
| Chicken, light meat (roasted) | 3 ounces | 0.08 |
| Chicken, dark meat (roasted) | 3 ounces | 0.16 |
| Beef (cooked) | 3 ounces | 0.16 |
| Broccoli (boiled) | 1/2 cup chopped | 0.10 |
| Asparagus (boiled) | 6 spears | 0.13 |
| Spinach (boiled) | 1/2 cup | 0.21 |
| Bread, whole wheat | 1 slice | 0.06 |
| Bread, white (enriched) | 1 slice | 0.08 |
*A 3-ounce serving of meat is about the size of a deck of cards.
Supplements
The most common forms of riboflavin available in supplements are riboflavin and riboflavin 5'-monophosphate. Riboflavin is most commonly found in multivitamin and vitamin B-complex preparations (27).
Toxicity
No toxic or adverse effects of high riboflavin intake in humans are known. Studies in cell culture indicate that excess riboflavin may increase the risk of DNA strand breaks in the presence of chromium (IV), a known carcinogen (28). This may be of concern to workers exposed to chrome, but no data in humans are available. High-dose riboflavin therapy has been found to intensify urine color to a bright yellow (flavinuria), but this is a harmless side effect. The Food and Nutrition Board did not establish a tolerable upper level of intake (UL) when the RDA was revised in 1998 (1).
Drug interactions
Several early reports indicated that women taking high-dose oral contraceptives (OC) had diminished riboflavin nutritional status. However, when investigators controlled for dietary riboflavin intake, no differences between OC users and non-users were found (1). Phenothiazine derivatives like the anti-psychotic medication chlorpromazine and tricyclic antidepressants inhibit the incorporation of riboflavin into FAD and FMN, as do the anti-malarial medication, quinacrine, and the cancer chemotherapy agent, adriamycin (4). Long-term use of the anti-convulsant, phenobarbitol may increase destruction of riboflavin, by liver enzymes, increasing the risk of deficiency (3).
Linus Pauling Institute Recommendation
The RDA for riboflavin (1.3 mg/day for men and 1.1 mg/day for women), which should prevent deficiency in most individuals, is easily met by eating a varied diet. Consuming a varied diet should supply 1.5 mg to 2 mg of riboflavin a day. Following the Linus Pauling Institute recommendation to take a multivitamin/multimineral supplement containing 100% of the Daily Values (DV) will ensure an intake of at least 1.7 mg of riboflavin/day.
Older adults (50 years of age and older)
Some experts in nutrition and aging feel that the RDA (1.3 mg/day for men and 1.1 mg/day for women) leaves little margin for error in people over 50 years of age (29, 30). A recent study of independently living people between 65 and 90 years of age found that almost 25% consumed less than the recommended riboflavin intake, and 10% had biochemical evidence of deficiency (31). Additionally, epidemiological studies of cataract prevalence indicate that riboflavin intakes of 1.6 to 2.2 mg/day may reduce the risk of developing age-related cataracts. Individuals whose diets may not supply adequate riboflavin, especially those over 50, should consider taking a multivitamin/multimineral supplement, which generally provides at least 1.7 mg of riboflavin/day.
Written in September 2002 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University
Updated in June 2007 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University
Reviewed in June 2007 by:
Donald B. McCormick, Ph.D.
F. E. Callaway Professor, Emeritus
Department of Biochemistry
Emory University School of Medicine
Copyright 2000-2010 Linus Pauling Institute
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