Vitamin B-2 (Riboflavin)

In the body, riboflavin is primarily found as an integral component of the coenzymes, flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN)

RIBOFLAVIN

Riboflavin is a water-soluble B-complex vitamin, also known as vitamin B-2.  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 also called flavins.  Enzymes that use a flavin coenzyme are called flavoproteins (2).

FUNCTION

Oxidation-reduction (redox) reactions: Living organisms derive most of their energy from oxidation-reduction (redox) reactions, which are processes involving the transfer of electrons. Flavin coenzymes participate in redox reactions in numerous metabolic pathways (3).  Flavins 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, flavins also participate in the metabolism of drugs and toxins (4).

Antioxidant functions:

Glutathione reductase

      is an 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.  See

diagram

      .  Glutathione peroxidase (a selenium-containing enzyme) requires two molecules of reduced glutathione to break down 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)

      .

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).

Nutrient interrelationships:

B-complex vitamins:

      Because flavoproteins are involved in the metabolism of several other vitamins (vitamin B-6, niacin,  and folic acid), severe riboflavin deficiency may impact many enzyme systems. Conversion of most naturally available vitamin B-6 to its coenzyme, 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 B-6 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 an FAD-dependent enzyme, which plays an important role in maintaining the specific folate coenzyme required to form methionine from homocysteine (See

diagram

      ).

Riboflavin and 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 deficient and iron deficient improves the response of iron-deficiency anemia to iron therapy(10).

DEFICIENCY

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), a moist, scaly skin inflammation (seborrheic dermatitis), 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 B-6 to its coenzyme form (PLP) and decreased conversion of tryptophan to niacin (see Nutrient Interrelationships).

Risk factors for riboflavin deficiency: The use of specialized light therapy to treat jaundice in newborns increases the destruction of riboflavin and is a recognized cause of riboflavin deficiency (6).  Alcoholics are at increased risk for riboflavin deficiency due to decreased intake, decreased absorption, and impaired utilization of riboflavin. Anorexic individuals rarely consume adequate riboflavin. Lactose intolerance may prevent people from consuming milk or dairy products, which are good sources of riboflavin. The conversion of riboflavin into FAD and FMN is impaired by hypothyroidism and adrenal insufficiency (3,4). 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 (11).

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 excess urinary excretion of riboflavin is seen at intake levels of approximately 1 mg/day (1).

Adult men of all ages:

      1.3 milligrams (mg) of riboflavin/day

Adult women of all ages:

    1.1 mg of riboflavin/day

DISEASE PREVENTION

Cataracts: 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 oxidative damage of lens proteins from light may lead to age-related cataract. Two case-control studies found significantly decreased risk of age-related cataract (33% to 51%) in men and women in the highest quintile (1/5 of the study population) of dietary riboflavin intakes (1.6 to 2.2 mg/day) compared with those in the lowest quintile (0.08 mg/day) (12). 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. Recently, 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 intake for riboflavin were 50% less likely to have cataracts than those in the lowest quintile (13). 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 (1.5 mg/day) and those in the lowest quintile (1.2 mg/day) (14). However, the range between the highest and lowest quintiles was small, and median intake levels for both were above the current RDA for riboflavin. 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.

DISEASE TREATMENT

Migraine headaches: Some evidence indicates that impaired mitochondrial oxygen metabolism in the brain may play a role in the pathology of migraine headaches.  As the precursor of the two flavin coenzymes (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 3 months on migraine prevention in 54 men and women with a history of recurrent migraine headaches.  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(15). It should be noted, however, that only about 25 mg of riboflavin can be absorbed in a single oral dose (16). 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.  Though these findings are preliminary, they suggest that riboflavin supplementation might be a useful adjunct to pharmacologic therapy with beta-blockers in migraine prevention (17).

FOOD SOURCES

Most plant and animal derived foods contain at least small quantities of riboflavin. Wheat flour and bread have been enriched with riboflavin (as well as thiamin, niacin, and iron) since 1943 in the U.S.  Data from large dietary surveys indicates that the average intake of riboflavin for men is about 2 mg/day and for women is about 1.5 mg/day, 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.  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 you eat frequently, search the USDA food composition database.

Food Serving Riboflavin (mg)
Milk (nonfat) 1 cup (8 ounces) 0.34
Cheddar cheese 1 ounce 0.11
Egg (cooked) 1 large 0.27
Almonds 1 ounce 0.24
Salmon (broiled) 3 ounces* 0.13
Halibut (broiled) 3 ounces 0.08
Chicken, light meat (roasted) 3 ounces 0.10
Chicken, dark meat (roasted) 3 ounces 0.18
Beef (cooked) 3 ounces 0.19
Broccoli (boiled or steamed) 1/2 cup chopped 0.09
Asparagus (boiled or steamed) 6 spears 0.13
Spinach (boiled or steamed) 1/2 cup 0.09
Fortified cereal 1 cup 0.59 to 2.27
Bread, whole wheat 1 slice 0.07
Bread, white (enriched) 1 slice 0.09

*A 3-ounce serving of meat is about the size of a deck of cards.

SAFETY

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 knowncarcinogen (18).  This may be of concern to workers exposed to chrome, but no data in humans is 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).

THE LINUS PAULING INSTITUTE RECOMMENDATION

The RDA for riboflavin (1.3 mg/day for men and 1.1 mg/day for women) is easily met by eating a varied diet, and should prevent deficiency in most individuals. Consuming a varied diet should supply 1.5 mg to 2 mg of riboflavin a day (see Food Sources).  Following the Linus Pauling Institute recommendation to take a multivitamin/multimineral supplement, containing 100 % of the Daily Values, 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 (19,20).  Additionally, epidemiologic 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.

RECENT RESEARCH

Riboflavin and preeclampsia (pregnancy induced hypertension):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) (21).   A recent study of 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, though decreased intracellular levels of flavin coenzymes could affect mitochondrial function, oxidative stress, and blood vessel dilation, which have all been associated with preeclampsia (22).

REFERENCES

  1. Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B-6, Vitamin B-12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academy Press, 1998: pages 87-122. (National Academy Press)
  2. Brody, T. Nutritional Biochemistry, 2nd Edition. San Diego, CA: Academic Press, 1999:  pages 609-613.
  3. McCormick, D.B. Riboflavin. In Shils, M. et al. Eds. Nutrition in Health and Disease, 9th Edition. Baltimore: Williams & Wilkins, 1999: pages 391-399.
  4. Rivlin, R.S. Riboflavin. In Ziegler, E.E. & Filer, L.J. Eds. Present Knowledge in Nutrition. Washington D.C.: ILSI Press, 1996: pages 167-173.
  5. Powers, H.J. Current knowledge concerning optimal nutrition status of riboflavin, niacin and pyridoxine. Proceedings of the Nutrition Society. 1999; volume 58: pages 434-440. (PubMed)
  6. Bohles, H. Antioxidative vitamins in prematurely and maturely born infants. International Journal of Vitamin and Nutrition Research. 1997; volume 67: pages 321-328.  (PubMed)
  7. McCormick, D.B. Two interconnected B vitamins: riboflavin and pyridoxine. Physiological Reviews. 1989; volume 69: pages 1170-1198.
  8. Lowik, M.R.H. et al. Interrelationships between riboflavin and vitamin B-6 among elderly people (Dutch Nutrition Surveillance System). International Journal of Vitamin and Nutrition Research. 1994; volume 64; pages 198-203.  (PubMed)
  9. Madigan, S.M. et al. Riboflavin and vitamin B-6 intakes and status and biochemical response to riboflavin supplementation in free-living elderly people. American Journal of Clinical Nutrition. 1998; volume 68: pages 389-395.  (PubMed)
  10. Powers, H.J. Riboflavin-iron interactions with particular emphasis on the gastrointestinal tract. Proceedings of the Nutrition Society. 1995; volume 54: pages 509-517. (PubMed)
  11. Soares, M.J. et al. The effect of exercise on the riboflavin status of adult men. British Journal of Nutrition. 1993; volume 69: pages 541-551.  (PubMed)
  12. Jaques, P.F. The potential preventive effects of vitamins for cataract and age-related macular degeneration. International Journal of Vitamin and Nutrition Research. 1999; volume 69: pages 198-205. (PubMed)
  13. Cumming, R.G. et al. Diet and cataract: the Blue Mountains Eye Study. Opthamology. 2000; volume 197: pages 450-456. (PubMed)
  14. Hankinson, S.E. et al. Nutrient intake and cataract extraction in women. British Medical Journal (BMJ). 1992; volume 305: pages 335-9.  (PubMed)
  15. Schoenen, J. et al. Effectiveness of high-dose riboflavin in migraine prophylaxis. Neurology. 1998; volume 50: pages 466-470.  (PubMed)
  16. Zempleni, J. et al. Pharmacokinetics of orally and intravenously administered riboflavin in healthy humans. American Journal of Clinical Nutrition. 1996; volume 63: pages 54-56. (PubMed)
  17. Sandor, P.S. et al. Prophylactic treatment of migraine with beta-blockers and riboflavin: differential effects on the intensity dependence of auditory evoked cortical potential. Headache. 2000; volume 40; pages 30-35.  (PubMed)
  18. Sugiyama, M. Role of physiological antioxidants in chromium (IV)-induced cellular injury. Free Radical Biology & Medicine. 1992; volume 12: pages 397-407. (PubMed)
  19. Blumberg, J. Nutritional needs of seniors. Journal of the American College of Nutrition. 1997; volume 16: pages 517-523.  (PubMed)
  20. Russell, R.M. & Suter, P.M. Vitamin requirements of elderly people: an update. American Journal of Clinical Nutrition.1993; volume 58: pages 4-14. (PubMed)
  21. Crombleholme, W.R. Obstetrics. In Tierney, L.M., McPhee, S.J.& Papadakis, M.A. Eds. Current Medical Treatment and Diagnosis, 37th Edition. Stamford, CT: Appleton and Lange, 1998: pages 731-734.
  22. Wacker, J. et al. Riboflavin deficiency and preeclampsia. Obstetrics and Gynecology. 2000; volume 96: pages 38-44.  (PubMed)

Add Comment

Your email address will not be published. Required fields are marked *

Be informed!

Sign up for newsletter