Nutritional summary

Function: Riboflavin is the precursor of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), which serve both as prosthetic groups and as cofactors for a wide range of enzymes important for beta-oxidation and oxidative phosphorylation. antioxidant defense, vitamin metabolism (folate, niacin, vitamins A, C, B6. and U12). amino acid utilization, hormone synthesis, and many other functions. Food sources: Milk and dairy products, meat, poultry and fish, cereals and bread and green vegetables each can provide at least one-sixth of recommended intakes per serving.




CH j



CH j

Figur« 10.11 Riboflavin

Requirements: Current RDAs for women arc I.lmgd. and for men. I.3mgd. Pregnancy, lactation, and increased energy intake and expenditure all increase requirements. Since only I 2 w eeks' requirements are stored, regular adequate intakes are important.

Deficiency: Prolonged low intakes cause cracking and swelling of the lips (cheilosis), cracking and inflammation of the angles of the mouth (angular stomatitis), dark-red colored tongue (glossitis), skin changes at other sites (seborrheic dermatitis), and normocyte anemia. Deficiency during infancy and childhood impairs growth. Excessive intake: There is little danger even when intakes exceed recommendation many times. Since excess riboflavin is lost rapidly, there is no additional benefit over recommended intake levels and stores will not increase.

Dietary sources

Foods contain free and beta-glucosylated riboflavin (Gregory, 1998) as well as FMN and FAD, some of the latter covalently bound to proteins. Riboflav in is heat-stable, but light- and a I kali-sensitive; the inactive form lumiflavin (7.8,10-trimethylisoall-oxa/ine) is a product of photodecom posit ion (Chastam and McCormick, ! 987). Best sources of riboflavin are milk and dairy products, meat, poultry and fish, green vegetables. cereals, and bread. Grain products in the L'S have to be fortified with 4 mg kg. Median intake in the US is about 2 mg d much of this from fortified foods and dietary supplements.

Figure 10.12 Lurwflavin is. a light-inacuvaied product of riboflavin

Digestion and absorption

Riboflavin is present in foods mostly (SO 90%) as FAD and FMN cofactors of proteins. Hydrochloric acid front the stomach readily releases the flavins that arc only loosely bound to their proteins. A small percentage of food flavin is bound to a histidyl-nitrogen or cysteinyl-sulfur and proteolysis results in the release of amino acid-linked 8-alpha-FAD which is biologically inactive. FMN is dephosphorylated to ribolla\ in by alkaline phosphatase (I t' ) in the small intestine. FAD is broken up by nucleotide pyrophosphatase (EC3.6.1.9) at the brush border of villous tip cells into AMP and FMN from which riboflavin can then be released (Byrd et ut.. 1985), Some of the riboflav in in plant-derived foods is present as beta-glucoside. which has to be cleaved by a bcta-glncosidase (possibly lactase) prior to absorption.

Fractional intestinal absorption of riboflavin and related compounds is high over a large range of intakes (75°.. of a 20,mg dose) and dcdincs with intakes beyond that (Zempleni et at, 19%),

Riboflav in is absorbed mainly from the jejunum, and only to a much lesser degree from the large intestine (Said et al., 2000). Uptake proceeds by a rapid process dependent on energy, but not on sodium or proton flux. At higher concentrations passive diffusion into the cnterocyte becomes increasingly relevant. Retention in the cnterocyte does not email metabolic modification of free riboflavin (Said and Ma. 1994). The maximal amount that can be absorbed from a single dose appears to be about 27 mg (Zempleni et al., 1996).

Phosphorylation of free riboflavin by riboflavin kinase (flavokinase. EC2.7.1.26: zinc) to FMN is critical for retaining riboflavin in the cnterocyte (Gastaldi et al., 2000). FMN can then be converted to FAD by ATPrFMN adenvly [transferase (FAD synthetase; EC2.7.7.2), About 60% of absorbed riboflavin is exported as FMN or FAD (Gastaldi et al.. 2000). It is not clear whether riboflavin and its metabolites !ea\e the enterocyte by simple diffusion or by another proccss.

Transport and cellular uptake

Blood circulation; FAD. riboflavin, and FMN are (in descending concentration order) the main forms in plasma; in severe malnutrition FAD concentration may be lower than FMN concentration (Capo-chichi et at.. 2000). Neither the plasma concentration of llavocoenzymes (around 79nmol l) nor of riboflavin concentration in plasma (around 13nmol/l) vanes much in response to different levels of intake (Zempleni et at.. 1996). Most riboflav in metabolites in plasma are associated with immunoglobulins. albumin, and other proteins (Innis et at.. 1985). Riboflav in is taken up into liver by an energy-dependent process (Said et al.. 1998), I ptakc into liver and other tissues first requires the hydrolysis of FAD and FMN to riboflavin (Lee and Ford, 1988). Some inactive metabolites such as 2'-hydroxycthyl flavin impede ccllular uptake of riboflavin by competition (Aw et al.. 19831.

The riboflavin carrier protein (RCP) mediates intracellular riboflavin transport (Schneider, 1996). RCP is expressed in placenta and in Sertoli and Levdig ceils of the testes and in spermatozoa. The chicken vitellogenin receptor imports very-low-density lipoprotein, riboflav in-binding protein, and alpha-2-macroglobulin into growing oocytes. The similarity of vitellogenin receptor and V'LDL receptor raises the question w hether the latter may contribute to the uptake of riboflav in-binding protein in humans (Schneider. 1996),

Materna-fetal transfer: Riboflav in-containing nucleotides have to be cleaved prior to uptake into syntrophoblasts via an as yet unknown carrier, RCP is critical for riboflavin transfer across the placental membrane and is inducible by estrogen. Antibodies against RCP reduce fertility (Adiga et al.. 1997).

Blood brain barrier: Riboflav in rapidly crosses from blood circulation into brain and is converted into FMN and FAD (Spector. 1980). Reverse transport is also readily possible. The carrier mechanisms involved in this transfer and their regulation arc not yet well understood.


Activation: Flavin cofactor synthesis occurs in liver and most other tissues, in the initial, rate limiting step the zinc-dependent riboflavin kinase (FC2.7.1.26) phosphorylates riboflavin. From FMN the more commonly used cofactor FAD is produced by FMN adenylyltransferase (EC2.7.7.2). This magnesium-dependent reaction links the phosphate group of the AMP moiety to the phosphate group of FMN. There is no information about the mechanism(s) whereby FMN or FAD becomes covalently bound to specific histidyl or cysteinyl residues of just a few of the numerous llavoproteins.



Flavokmase (zinc, magnesium)y

/""Alkaline phosphatase p (zinc, magnesium)


Flavinmononucteotide 0 (FMN)

Nucleotide pyrophosphatase (magnesium)

FMN adenylyt transferase (magnesium) PP,


Flavinadenine dinucíeofide (FAD)

FMN adenylyt transferase (magnesium) PP,

Flavinadenine dinucíeofide (FAD)

Figura 10.13 Riboflavin irtfi.ibolism

Catabolism: Intracellular FAD can be cleaved into FMN and AMP by FAD pyrophosphatase (EC3.6.I.1.8), and FMN can be dephosphorylated by alkaline phosphatase. Some of the free intracellular riboflavin is metabolized to 7-alpha-hydromethyl riboflavin and 8-alpha-hydromethyl riboflavin by microsomal oxidation. The mechanism for

Figure 10.14 The riboflavin catabcihtc 10-(2'-hydi-ci>cyrthyt) flavin at is as an aiuiviramin

production of the antiv iiamin 10-{2'-hydroxyethyl) flavin, which is present in human (and bovine) milk. 1» nol known (Aw el al.. 1983).

In the few instances where the flavin moiety is covalently hound the intracellular degradation of the protein may generate 8-alpha-S-cysteinyl riboflavin. This metabolite is converted to 8-aIpha-suIfonylriboflavin upon release from IAD-containing amine oxidase (monoamine oxidase, EC 1.4,3.4, Chastain and McCormick. 19K7). Htstidine-linked flavins arc metabolized to histidy) riboflavine or related catabolites.


There is general agreement that riboflavin is not stored in specific compartments and ingested vitamin is turned over and excreted with a half-life of a few days. Several metabolites, including some of the protein-bound FMN and FAD, are reutilizcd upon protein turnover and pro\ ¡de a riboflav in pool that can cover needs during times of low intake. Unfortunately, information is lacking on the precise size of this pool in Ji lièrent states of repletion and how much biologically active vitamin is released per day in the absence of dietary intakes.

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