Dietary Reference Values for riboflavin
2017; Wiley; Volume: 15; Issue: 8 Linguagem: Inglês
10.2903/j.efsa.2017.4919
ISSN1831-4732
AutoresDominique Turck, Jean‐Louis Bresson, Barbara Burlingame, Tara Dean, Susan J. Fairweather‐Tait, Marina Heinonen, Karen Ildico Hirsch‐Ernst, Inge Mangelsdorf, Harry J McArdle, Androniki Naska, Grażyna Nowicka, Kristina Pentieva, Yolanda Sanz, Alfonso Siani, Anders Sjödin, Martin Stern, Daniel Tomé, Henk Van Loveren, Marco Vinceti, Peter Willatts, Christel Lamberg‐Allardt, Hildegard Przyrembel, Inge Tetens, Céline Dumas, Lucia Fabiani, Annette Cecilia Forss, Sofia Ioannidou, Monika Neuhäuser‐Berthold,
Tópico(s)Nutritional Studies and Diet
ResumoEFSA JournalVolume 15, Issue 8 e04919 Scientific OpinionOpen Access Dietary Reference Values for riboflavin EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA), EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA)Search for more papers by this authorDominique Turck, Dominique TurckSearch for more papers by this authorJean-Louis Bresson, Jean-Louis BressonSearch for more papers by this authorBarbara Burlingame, Barbara BurlingameSearch for more papers by this authorTara Dean, Tara DeanSearch for more papers by this authorSusan Fairweather-Tait, Susan Fairweather-TaitSearch for more papers by this authorMarina Heinonen, Marina HeinonenSearch for more papers by this authorKaren Ildico Hirsch-Ernst, Karen Ildico Hirsch-ErnstSearch for more papers by this authorInge Mangelsdorf, Inge MangelsdorfSearch for more papers by this authorHarry J McArdle, Harry J McArdleSearch for more papers by this authorAndroniki Naska, Androniki NaskaSearch for more papers by this authorGrażyna Nowicka, Grażyna NowickaSearch for more papers by this authorKristina Pentieva, Kristina PentievaSearch for more papers by this authorYolanda Sanz, Yolanda SanzSearch for more papers by this authorAlfonso Siani, Alfonso SianiSearch for more papers by this authorAnders Sjödin, Anders SjödinSearch for more papers by this authorMartin Stern, Martin SternSearch for more papers by this authorDaniel Tomé, Daniel ToméSearch for more papers by this authorHenk Van Loveren, Henk Van LoverenSearch for more papers by this authorMarco Vinceti, Marco VincetiSearch for more papers by this authorPeter Willatts, Peter WillattsSearch for more papers by this authorChristel Lamberg-Allardt, Christel Lamberg-AllardtSearch for more papers by this authorHildegard Przyrembel, Hildegard PrzyrembelSearch for more papers by this authorInge Tetens, Inge TetensSearch for more papers by this authorCéline Dumas, Céline DumasSearch for more papers by this authorLucia Fabiani, Lucia FabianiSearch for more papers by this authorAnnette Cecilia Forss, Annette Cecilia ForssSearch for more papers by this authorSofia Ioannidou, Sofia IoannidouSearch for more papers by this authorMonika Neuhäuser-Berthold, Monika Neuhäuser-BertholdSearch for more papers by this author EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA), EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA)Search for more papers by this authorDominique Turck, Dominique TurckSearch for more papers by this authorJean-Louis Bresson, Jean-Louis BressonSearch for more papers by this authorBarbara Burlingame, Barbara BurlingameSearch for more papers by this authorTara Dean, Tara DeanSearch for more papers by this authorSusan Fairweather-Tait, Susan Fairweather-TaitSearch for more papers by this authorMarina Heinonen, Marina HeinonenSearch for more papers by this authorKaren Ildico Hirsch-Ernst, Karen Ildico Hirsch-ErnstSearch for more papers by this authorInge Mangelsdorf, Inge MangelsdorfSearch for more papers by this authorHarry J McArdle, Harry J McArdleSearch for more papers by this authorAndroniki Naska, Androniki NaskaSearch for more papers by this authorGrażyna Nowicka, Grażyna NowickaSearch for more papers by this authorKristina Pentieva, Kristina PentievaSearch for more papers by this authorYolanda Sanz, Yolanda SanzSearch for more papers by this authorAlfonso Siani, Alfonso SianiSearch for more papers by this authorAnders Sjödin, Anders SjödinSearch for more papers by this authorMartin Stern, Martin SternSearch for more papers by this authorDaniel Tomé, Daniel ToméSearch for more papers by this authorHenk Van Loveren, Henk Van LoverenSearch for more papers by this authorMarco Vinceti, Marco VincetiSearch for more papers by this authorPeter Willatts, Peter WillattsSearch for more papers by this authorChristel Lamberg-Allardt, Christel Lamberg-AllardtSearch for more papers by this authorHildegard Przyrembel, Hildegard PrzyrembelSearch for more papers by this authorInge Tetens, Inge TetensSearch for more papers by this authorCéline Dumas, Céline DumasSearch for more papers by this authorLucia Fabiani, Lucia FabianiSearch for more papers by this authorAnnette Cecilia Forss, Annette Cecilia ForssSearch for more papers by this authorSofia Ioannidou, Sofia IoannidouSearch for more papers by this authorMonika Neuhäuser-Berthold, Monika Neuhäuser-BertholdSearch for more papers by this author First published: 07 August 2017 https://doi.org/10.2903/j.efsa.2017.4919Citations: 16 Correspondence: nda@efsa.europa.eu Requestor: European Commission Question number: EFSA-Q-2011-01222 Panel members: Jean-Louis Bresson, Barbara Burlingame, Tara Dean, Susan Fairweather-Tait, Marina Heinonen, Karen Ildico Hirsch-Ernst, Inge Mangelsdorf, Harry J McArdle, Androniki Naska, Monika Neuhäuser-Berthold, Grażyna Nowicka, Kristina Pentieva, Yolanda Sanz, Alfonso Siani, Anders Sjödin, Martin Stern, Daniel Tomé, Dominique Turck, Henk Van Loveren, Marco Vinceti and Peter Willatts. Acknowledgements: The Panel wishes to thank EFSA staff: Krizia Ferrini and Olga Vidal Pariente for the support provided to this scientific opinion. Adopted: 27 June 2017 This publication is linked to the following EFSA Supporting Publications article: http://onlinelibrary.wiley.com/doi/10.2903/sp.efsa.2017.EN-1268/full AboutSectionsPDF ToolsExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Abstract Following a request from the European Commission, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) derives dietary reference values (DRVs) for riboflavin. The Panel considers that the inflection point in the urinary riboflavin excretion curve in relation to riboflavin intake reflects body saturation and can be used as a biomarker of adequate riboflavin status. The Panel also considers that erythrocyte glutathione reductase activation coefficient is a useful biomarker, but has limitations. For adults, the Panel considers that average requirements (ARs) and population reference intakes (PRIs) can be determined from the weighted mean of riboflavin intake associated with the inflection point in the urinary riboflavin excretion curve reported in four intervention studies. PRIs are derived for adults and children assuming a coefficient of variation of 10%, in the absence of information on the variability in the requirement and to account for the potential effect of physical activity and the methylenetetrahydrofolate reductase 677TT genotype. For adults, the AR and PRI are set at 1.3 and 1.6 mg/day. For infants aged 7–11 months, an adequate intake of 0.4 mg/day is set by upward extrapolation from the riboflavin intake of exclusively breastfed infants aged 0–6 months. For children, ARs are derived by downward extrapolation from the adult AR, applying allometric scaling and growth factors and considering differences in reference body weight. For children of both sexes aged 1–17 years, ARs range between 0.5 and 1.4 mg/day, and PRIs between 0.6 and 1.6 mg/day. For pregnant or lactating women, additional requirements are considered, to account for fetal uptake and riboflavin accretion in the placenta during pregnancy or the losses through breast milk, and PRIs of 1.9 and 2.0 mg/day, respectively, are derived. Summary Following a request from the European Commission, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) was asked to deliver a scientific opinion on dietary reference values (DRVs) for the European population, including vitamin B2. The Panel considers in this Scientific Opinion that vitamin B2 is riboflavin. Riboflavin or 7,8-dimethyl-10-ribityl-isoalloxazine, is a water-soluble compound naturally present in food of plant and animal origin as free riboflavin and, mainly, as the biologically active derivatives flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). Riboflavin is the integral part of the coenzymes FAD and FMN that act as the cofactors of a variety of flavoprotein enzymes such as glutathione reductase or pyridoxamine phosphate oxidase (PPO). FAD and FMN act as proton carriers in redox reactions involved in energy metabolism, metabolic pathways and formation of some vitamins and coenzymes. In particular, riboflavin is involved in the metabolism of niacin and vitamin B6 and FAD is also required by the methylenetetrahydrofolate reductase (MTHFR) in the folate cycle and thereby is involved in homocysteine metabolism. Signs of riboflavin deficiency are unspecific and include sore throat, hyperaemia and oedema of the pharyngeal and oral mucous membranes, cheilosis, glossitis (magenta tongue), and normochromic normocytic anaemia characterised by erythroid hypoplasia and reticulocytopenia. No tolerable upper intake level has been set for riboflavin. Dietary riboflavin associated with food protein is hydrolysed to free riboflavin and its absorption mainly takes place in the proximal small intestine through carrier-mediated, saturable transport process. The Panel considers an absorption efficiency of dietary riboflavin of 95%. Free riboflavin transported into enterocytes is subjected to phosphorylation to form FMN, subsequently converted to FAD. From the small intestine, riboflavin enters the plasma, where FAD is reported to be the major form. The uptake of riboflavin into the cells of organs such as the liver is facilitated and may require specific carriers. Absorbed riboflavin appears partly in the plasma, and partly is sequestered by the liver on the first pass through the portal vein from the gut. There is a positive transfer of riboflavin from the pregnant woman to the fetus. Most of the riboflavin in tissues including erythrocytes exists predominantly as FAD and FMN, covalently bound to enzymes. Unbound FAD and FMN are rapidly hydrolysed to free riboflavin that diffuses from cells and is excreted. When riboflavin is absorbed in excess, it is catabolised to numerous metabolites and little is stored in the body tissues. Urine is the main route for elimination of riboflavin. The Panel reviewed possible biomarkers of riboflavin status and intake, i.e. urinary excretion of riboflavin, erythrocyte glutathione reductase activation coefficient (EGRAC), plasma and erythrocyte riboflavin, FAD and FMN, as well as PPO activity and activation coefficient. The Panel considers that the inflection point in the mean urinary riboflavin excretion curve in relation to riboflavin intake reflects body saturation and can be used to indicate adequate riboflavin status. The Panel also considers that EGRAC is a useful biomarker of riboflavin status and that EGRAC of 1.3 or less indicates adequate riboflavin status in all population groups. However, the Panel considers that the data on the relationship between riboflavin intake and EGRAC cannot be used alone to set DRVs for riboflavin, but can be used in support of data on the inflection in the urinary excretion curve in view of setting DRVs for riboflavin. The Panel also notes that riboflavin status is modified by physical activity as urinary excretion of riboflavin is (generally) decreased and EGRAC increased when physical activity is increased, suggesting higher utilisation of riboflavin with increased energy expenditure. However, there is a lack of experimental data showing a clear quantitative relationship between riboflavin status biomarkers (urinary excretion of riboflavin and EGRAC) and energy expenditure (or physical activity). In addition, the Panel considers that relationship between riboflavin intake and biomarkers of riboflavin status is also influenced by MTHFR C677T polymorphism, as homozygosity for the T allele can increase the individual requirement for riboflavin, although the extent of this increase cannot be defined. After having reviewed the existing evidence, the Panel concludes that available data on intake of riboflavin and health outcomes cannot be used to derive DRVs for riboflavin. The Panel notes that new scientific data have become available for adults since the publication of the Scientific Committee for Food (SCF) report in 1993, and considers that updated average requirements (ARs) and population reference intake (PRIs) can be set for adults, children, pregnant and lactating women. For adults, the Panel considers that an AR of 1.3 mg/day (after rounding) can be determined from the weighted mean of riboflavin intake associated with the inflection point in the mean urinary riboflavin excretion curve in relation to riboflavin intake as reported in four intervention studies in different non-European Union (EU) countries. The Panel considers that the potential effect of physical activity and of MTHFR 677TT genotype on riboflavin requirement is covered by the data presented from the studies considered, thus is accounted for in the assumed the coefficient of variation (CV) applied to set the PRI for riboflavin. A CV of 10% was used to calculate PRIs from the ARs for adults, i.e. 1.6 mg/day after rounding, and the same CV was used for all other population groups. The Panel considers that there is no indication of different riboflavin requirement according to sex or between younger and older adults, and sets the same DRV for men and women (without correction per difference in body weight) of all ages. For all infants aged 7–11 months, in the absence of sufficient data to set an AR, the Panel sets an AI of 0.4 mg/day based on the estimated intake of riboflavin of exclusively breastfed infants from birth to six months, and upward extrapolation by allometric scaling (on the assumption that riboflavin requirement is related to metabolically active body mass), taking into account the difference in reference body weight. For children aged 1–17 years, the Panel sets ARs by downward extrapolation from the AR of adults, by allometric scaling (on the assumption that riboflavin requirement is related to metabolically active body mass), applying growth factors and taking into account the differences in reference body weight. The Panel considers unnecessary to set sex-specific ARs and PRIs for boys and girls of all ages. The Panel sets ARs ranging from 0.5 (children aged 1–3 years) to 1.4 mg/day (children aged 15–17 years) and PRIs ranging from 0.6 (children aged 1–3 years) to 1.6 mg/day (children aged 15–17 years). For pregnant women, the Panel considers that data are insufficient to estimate the additional needs for dietary riboflavin during pregnancy based on fetal uptake and riboflavin accretion in the placenta during pregnancy. The Panel sets an AR of 1.5 mg/day, calculated by allometric scaling from the AR for non-pregnant women, considering the mean gestational increase in body weight of 12 kg, and also sets a PRI of 1.9 mg/day. For lactating women, an additional riboflavin requirement of 0.31 mg/day is calculated considering the secretion of riboflavin into milk during lactation (0.291 mg/day), the mean milk transfer during the first six months of lactation in exclusively breastfeeding women (0.8 L/day), and an absorption efficiency of 95%. An AR of 1.7 mg/day is calculated by the Panel, considering the additional requirement above the AR of non-lactating women, and a PRI of 2 mg/day is set for lactating women. Based on data from 13 surveys in nine countries of the EU, riboflavin intake mean estimates ranged across countries from 0.6 to 1.2 mg/day in infants (< 1 year), from 0.9 to 1.4 mg/day in children aged 1 to < 3 years, from 1 to 1.8 mg/day in children aged 3 to < 10 years, and from 1.2 to 2.2 mg/day in children aged 10 to < 18 years. Riboflavin intake mean estimates ranged between 1.4 and 2.2 mg/day in adults. Background as provided by the European Commission The scientific advice on nutrient intakes is important as the basis of Community action in the field of nutrition, for example such advice has in the past been used as the basis of nutrition labelling. The Scientific Committee for Food (SCF) report on nutrient and energy intakes for the European Community dates from 1993. There is a need to review and if necessary to update these earlier recommendations to ensure that the Community action in the area of nutrition is underpinned by the latest scientific advice. In 1993, the SCF adopted an opinion on the nutrient and energy intakes for the European Community.1 The report provided Reference Intakes for energy, certain macronutrients and micronutrients, but it did not include certain substances of physiological importance, for example dietary fibre. Since then new scientific data have become available for some of the nutrients, and scientific advisory bodies in many European Union (EU) Member States and in the United States have reported on recommended dietary intakes. For a number of nutrients these newly established (national) recommendations differ from the reference intakes in the SCF (1993) report. Although there is considerable consensus between these newly derived (national) recommendations, differing opinions remain on some of the recommendations. Therefore, there is a need to review the existing EU Reference Intakes in the light of new scientific evidence, and taking into account the more recently reported national recommendations. There is also a need to include dietary components that were not covered in the SCF opinion of 1993, such as dietary fibre, and to consider whether it might be appropriate to establish reference intakes for other (essential) substances with a physiological effect. In this context, the EFSA is requested to consider the existing Population Reference Intakes (PRIs) for energy, micro- and macronutrients and certain other dietary components, to review and complete the SCF recommendations, in the light of new evidence, and in addition advise on a PRI for dietary fibre. For communication of nutrition and healthy eating messages to the public, it is generally more appropriate to express recommendations for the intake of individual nutrients or substances in food-based terms. In this context, the European Food Safety Authority (EFSA) is asked to provide assistance on the translation of nutrient-based recommendations for a healthy diet into food-based recommendations intended for the population as a whole. Terms of reference as provided by the European Commission In accordance with Article 29 (1)(a) and Article 31 of Regulation (EC) No. 178/2002, the Commission requests EFSA to review the existing advice of the SCF on PRIs for energy, nutrients and other substances with a nutritional or physiological effect in the context of a balanced diet which, when part of an overall healthy lifestyle, contribute to good health through optimal nutrition. In the first instance, the EFSA is asked to provide advice on energy, macronutrients and dietary fibre. Specifically advice is requested on the following dietary components: Carbohydrates, including sugars; Fats, including saturated fatty acids, polyunsaturated fatty acids and monounsaturated fatty acids, trans fatty acids; Protein; Dietary fibre. Following on from the first part of the task, the EFSA is asked to advise on PRIs of micronutrients in the diet and, if considered appropriate, other essential substances with a nutritional or physiological effect in the context of a balanced diet which, when part of an overall healthy lifestyle, contribute to good health through optimal nutrition. Finally, the EFSA is asked to provide guidance on the translation of nutrient based dietary advice into guidance, intended for the European population as a whole, on the contribution of different foods or categories of foods to an overall diet that would help to maintain good health through optimal nutrition (food-based dietary guidelines). Assessment 1 Introduction In 1993, the SCF adopted an opinion on the nutrient and energy intakes for the European Community (SCF, 1993). For riboflavin, the SCF set average requirements (ARs) and PRIs for men and women. PRIs were also set for infants and children as well as for pregnant or lactating women. The purpose of this Opinion is to review dietary reference values (DRVs) for vitamin B2. In this Opinion, the Panel considers that vitamin B2 is the name of the compound riboflavin. 2 Definition/category 2.1 Chemistry Flavins (from Latin flavin, 'yellow') is the name of a group of water-soluble yellow pigments to which riboflavin, flavin mononucleotide (FMN), and flavin adenine dinucleotide (FAD) belong. Riboflavin, or 7,8-dimethyl-10-ribityl-isoalloxazine, is the tricyclic ring isoalloxazine bound to a ribityl side chain (IUPAC name: 7,8-Dimethyl-10-[(2S,3S,4R)-2,3,4,5-tetrahydroxypentyl]benzo[g]pteridine-2,4-dione) (Figure 1). Riboflavin is water-soluble. In the diet, it is naturally present as free riboflavin and, mainly, as the biologically active derivatives FMN and FAD (Figure 1) (Powers, 2003; Said and Ross, 2012). FMN is also called riboflavin-5-phosphate (Merrill et al., 1981). All three compounds are present in foods of plant or animal origin (Section 3.1). Riboflavin-binding proteins have been found in egg white and yolk (Zanette et al., 1984; White and Merrill, 1988), as well as in cow milk (Kanno et al., 1991). Although relatively heat-stable, riboflavin is readily degraded by light in solutions (Section 2.2.2.1). Riboflavin (E 101(i)) and riboflavin 5′-phosphate sodium (E 101(ii)) are also used as food colours (EFSA ANS Panel, 2013). In this Opinion, the Panel used the terms 'total riboflavin' to refer explicitly to the sum of the three components (riboflavin, FMN and FAD) and 'free riboflavin' whenever it is necessary to make a distinction from FMN or FAD. Figure 1Open in figure viewerPowerPoint Chemical structures of riboflavin, FMN and FAD Molecular masses: riboflavin: 376.4 g/mol; FMN: 456.3 g/mol, FAD: 785.6 g/mol. 2.2 Function of the nutrient 2.2.1 Biochemical functions Riboflavin is the integral part of the coenzymes FAD and FMN that act as the cofactors of flavoprotein enzymes involved in a variety of reactions. FAD and FMN act as proton carriers in redox reactions involved in energy metabolism (Section 2.5), metabolic pathways and the formation of some vitamins and coenzymes (McCormick, 2000; SCF, 2000; Said and Ross, 2012). In particular, riboflavin is involved in the metabolism of niacin and vitamin B6 (McCormick, 1989, 2000; EFSA NDA Panel, 2014a, 2016). FAD is also required as a cofactor for the methylenetetrahydrofolate reductase (MTHFR; EC 1.7.99.5) that is a key enzyme in the folate cycle (EFSA NDA Panel, 2015b) and it is required for the formation of 5-methyltetrahydrofolate which, in turn, is involved in the remethylation of homocysteine to methionine (McKinley et al., 2001). The enzyme glutathione reductase (EC 1.8.1.7) is using FAD as a cofactor to catalyse the reduction of the oxidised form glutathione disulfide (GSSG) to the sulfhydryl form glutathione (GSH), a critical step in maintaining the reducing environment of the cell. In people with glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common enzyme disorder caused by an enzyme defect, with an estimated frequency of 0.4% of all births in the EU (WHO Working Group, 1989; Cappellini and Fiorelli, 2008), glutathione reductase has an increased avidity for FAD, leading to high in vitro activity. Another enzyme, pyridoxamine phosphate oxidase (PPO, EC 1.4.3.5.) is FMN-dependent, is involved in the conversion of pyridoxine and pyridoxamine to the coenzyme pyridoxal phosphate and is present in various tissues including erythrocytes (Mushtaq et al., 2009). The activity of glutathione reductase in erythrocyte (EGR) and that of PPO are discussed in Sections 2.4.2 and 2.4.4. 2.2.2 Health consequences of deficiency and excess 2.2.2.1 Deficiency Riboflavin deficiency (ariboflavinosis) is most often accompanied by other nutrient deficiencies, and was reported in populations from both developed and developing countries (Venkataswamy, 1967; Komindr and Nichoalds, 1980; Nichoalds, 1981). Clinical signs of riboflavin deficiency reported in humans (IOM, 1998) are unspecific and include, e.g. sore throat, hyperaemia and oedema of the pharyngeal and oral mucous membranes, cheilosis, glossitis (magenta tongue), seborrhoeic dermatitis, skin lesions including angular stomatitis (as reported in (Horwitt et al., 1950)) and normochromic normocytic anaemia characterised by erythroid hypoplasia and reticulocytopenia (Lane and Alfrey, 1965). The correction of riboflavin deficiency improved haematologic markers in Gambian adults (Fairweather-Tait et al., 1992); the relationship between riboflavin status and haematologic markers is further described in Sections 2.3.7 and 2.4.2. Due to the photosensitivity of riboflavin, phototherapy used to treat hyperbilirubinemia in newborns was also associated with low riboflavin status as apparent by increases of erythrocyte glutathione reductase activation coefficient (EGRAC) values with the duration of phototherapy (see Section 2.4.2 on EGRAC) (Gromisch et al., 1977; Tan et al., 1978; Hovi et al., 1979; Parsons and Dias, 1991). The maximum absorption spectrum of riboflavin is at a wavelength similar to that at which the degradation of bilirubin occurs (Gromisch et al., 1977). A woman with riboflavin deficiency (indicated by an EGRAC of 2.81), although no clinical symptoms of deficiency were reported, gave birth to a child with malformations of the urinary tract and with the clinical and biochemical signs of multiple acyl-coenzyme A (CoA) dehydrogenase deficiency (MADD) due to a heterozygous deletion of the solute carrier SLC52A1 gene in the mother that codes for the human riboflavin transporter 1 (hRFT1) (Chiong et al., 2007; Ho et al., 2011). 2.2.2.2 Excess A tolerable upper intake level (UL) for riboflavin could not be derived by the SCF because there was not sufficient clinical evidence for adverse effects of 'high' riboflavin intakes (SCF, 2000). No adverse effects from 'high' riboflavin intakes from food or supplements have been reported (Rivlin, 2010). The Panel notes that revising the UL for riboflavin is not within the scope of the present Opinion. 2.3 Physiology and metabolism 2.3.1 Intestinal absorption Dietary FMN and FAD associated with food protein are hydrolysed to free riboflavin (Merrill et al., 1981; Nichoalds, 1981). Acidification in the stomach releases the non-covalently bound coenzymes FAD and FMN, which are also hydrolysed to free riboflavin by non-specific phosphatases of the brush border and basolateral membranes of enterocytes in the upper small intestine (Merrill et al., 1981; Said and Ross, 2012). Absorption of free riboflavin mainly takes place in the proximal small intestine through a carrier-mediated, saturable transport process (Jusko and Levy, 1967; Rivier, 1973; Meinen et al., 1977; Merrill et al., 1981; Daniel et al., 1983; Said and Ma, 1994; IOM, 1998; Said and Ross, 2012). A carrier-mediated absorption of riboflavin is also present in the colon (Sorrell et al., 1971; Yuasa et al., 2000; Said and Ross, 2012). A small amount of riboflavin circulates via the enterohepatic system (Said and Ross, 2012). The absorbed quantity of oral doses of riboflavin (assessed by the urinary recovery of riboflavin) linearly increases according to intake up to about 25–30 mg riboflavin (Levy and Jusko, 1966; Jusko and Levy, 1967) (also reported in reviews (Jusko and Levy, 1975; Merrill et al., 1981)). This was confirmed by the pharmacokinetics study by Zempleni et al. (1996) using oral riboflavin doses, which calculated the maximum amount of riboflavin that can be absorbed as about 27 mg. IOM (1998) based its discussion on bioavailability of riboflavin on Zempleni et al. (1996), which showed that absorption from the gut lumen was 95% complete within 4.4 h. In a study in 20 healthy women using 13C-labelled riboflavin in semiskimmed milk or 15N-labelled free riboflavin and FMN in spinach soup and urinary monitoring, there was no significant difference in true absorption between the spinach meal and the milk meal (Dainty et al., 2007). Prevalence of riboflavin deficiency is high in chronic alcoholics (Said and Ross, 2012), and the proposed mechanism investigated in animals and in vitro is that ethanol consumption inhibits the release of riboflavin from dietary FMN and FAD and its absorption (Pinto et al., 1987). A significant negative association between dietary phytate forms and apparent absorption of dietary riboflavin (−0.86, p < 0.05) was observed in ileostomy patients (Agte et al., 2005). The Panel notes that the absorbed quantity of riboflavin linearly increases up to an intake of 25–30 mg, and that absorption efficiency of dietary riboflavin is 95%. 2.3.2 Transport Free riboflavin transported into enterocytes is subjected to adenosine triphosphate (ATP)-dependent phosphorylation by the cytosolic flavokinase (EC 2.7.1.26) to form FMN subsequently converted to FAD by the FAD-dependent FAD synthetase (EC 2.7.7.2). Free riboflavin, FMN and FAD are transported in plasma bound to albumin and to immunoglobulins (Ig) (IgA, IgG and IgM), as shown in healthy subjects (Innis et al., 1985) and in patients (Innis et al., 1986). Hustad et al. (2002) (Section 2.4.3.1) reported FAD as the major form in plasma in healthy individuals compared to free riboflavin or FMN (median concentrations were 74, 10.5 and 6.6 nmol/L, respectively). FAD concentration in erythrocyte was reported to be higher than that of FMN (medians of 469 and 44 nmol/L respectively, with only traces of free
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