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Page 286 Balasubramaniam et al. J Transl Genet Genom 2020;4:285-306 I http://dx.doi.org/10.20517/jtgg.2020.34

INTRODUCTION
Riboflavin is the precursor of metabolically active flavocoenzymes which are utilized as cofactors for
approximately 90 flavoproteins in numerous enzymatic reactions as either flavin adenine dinucleotide (FAD)
[1]
(84%) or flavin mononucleotide (FMN) (16%) . These flavoproteins (enzymes using flavocoenzymes)
including dehydrogenases, oxidases, monooxygenases, and reductases play critical roles in mitochondrial
electron transport chain, mitochondrial and peroxisomal β-oxidation of fatty acids, citric acid cycle, redox
[2,3]
homeostasis, nitric oxide synthases, and branched-chain amino acid (BCAA) catabolism . They are also
[2]
involved in chromatin remodeling, DNA repair, protein folding, apoptosis biosynthesis or regulation of
other essential cofactors and hormones, including coenzyme A, coenzyme Q, heme, pyridoxal 5’-phosphate,
steroids, and thyroxine; and metabolism of other B vitamins (folate, pyridoxine, and niacin) and P450
[1,4]
enzymes .
Riboflavin, as with other water-soluble B vitamins, must be obtained through diet as mammals have lost the
ability to synthesize this molecule. Endogenous synthesis of riboflavin by microflora in the large intestine
[5]
may contribute but to a lesser extent . Hence, adequate dietary intake from major sources such as milk and
dairy products, eggs, seafood, poultry, lean meat, cereals, and vegetables is imperative. The recommended
daily allowance of riboflavin on average is 1.3 mg/day for adult men and 1.1 mg/day for women, with
[5]
variations depending on age and reproductive status including pregnancy and lactation .

RIBOFLAVIN METABOLISM AND TRANSPORT
Riboflavin ingested in diet exists either as free riboflavin, predominantly found in milk and eggs, or its
protein bound form as flavoproteins including FAD and FMN, which must be released from the carrier
proteins to which they are bound. The latter occurs through dietary protein denaturation in the stomach
and subsequent hydrolysis to free riboflavin by alkaline phosphatases and FMN/FAD pyrophosphatases in
[6]
the ileal brush border to be absorbed in the small intestine [Figure 1]. Next, free riboflavin is transported
into the enterocytes via carrier-mediated uptake by RFVT3 (previously hRFT2, encoded by SLC52A3),
[7]
which functions primarily to absorb riboflavin from dietary intake . This saturable uptake process occurs
[8]
at the apical membrane and is reported to be linear up to approximately 30 mg riboflavin per meal ,
following which little additional absorption of riboflavin occurs [9,10] .
After cellular uptake, free riboflavin undergoes adenosine triphosphate (ATP)-dependent phosphorylation
by riboflavin kinase (RFK) (EC 2.7.1.26), a ubiquitous rate-limiting flavokinase, to form FMN, which is
consequently adenylated to FAD by FAD synthase (FADS) (EC 2.7.7.2). Riboflavin may subsequently be
released into the portal blood and to the liver in its free form or as FMN after being transported by RFVT1
(previously hRFT1) and RFVT2 (previously hRTF3), encoded by SLC52A1 and SLC52A2, respectively,
and embedded within the basolateral membrane of the enterocytes . Apart from being expressed in the
[5]
gastrointestinal system, RFVT1 is also detected in the placenta where it transports maternal riboflavin to
the fetus. RFVT2-mediated transport allows riboflavin uptake into the brain where it is highly expressed,
[7]
and additionally in endocrine organs such as the pancreas, liver, and muscle .
Circulating plasma riboflavin is either bound to albumin and immunoglobulins or is converted into its
coenzyme forms in erythrocytes or leukocytes. Unbound flavins are rapidly hydrolyzed to free riboflavin
and excreted in urine. There is little or no storage of riboflavin in the body; hence, any intake in excess of
tissue requirements or which surpasses renal reabsorption is eliminated in the urine as riboflavin or its
catabolites 7-alpha-hydroxy riboflavin, 10-hydroxyethylflavin, and lumiflavin [5,11] . As a result, riboflavin has
a relatively low toxicity even at supra-pharmacological doses .
[5]