Introduction to Human Nutrition

The Vitamins 157

and key enzymes in fatty acid and amino acid oxida-
tion, and the citric acid cycle. The fl avin coenzymes
remain bound to the enzyme throughout the catalytic
cycle. The majority of fl avoproteins have FAD as the
prosthetic group rather than ribofl avin phosphate;
some have both fl avin coenzymes and some have
other prosthetic groups as well.
Flavins can undergo a one-electron reduction to
the semiquinone radical or a two-electron reduction
to dihydrofl avin. In some enzymes formation of dihy-
drofl avin occurs by two single-electron steps, with
intermediate formation of the semiquinone radical.
Dihydrofl avin can be oxidized by reaction with a
substrate, NAD(P)+, or cytochromes in a variety of
dehydrogenases, or can react with molecular oxygen
in oxygenases and mixed function oxidases
(hydroxylases).

Flavins and oxidative stress
Reoxidation of the reduced fl avin in oxygenases and
mixed function oxidases proceeds by way of formation
of the fl avin radical and fl avin hydroperoxide, with the
intermediate generation of superoxide and perhy-
droxyl radicals and hydrogen peroxide. Because of this,
fl avin oxidases make a signifi cant contribution to the
total oxidant stress of the body. Overall, some 3–5% of
the daily consumption of about 30 mol of oxygen by
an adult is converted to singlet oxygen, hydrogen
peroxide, and superoxide, perhydroxyl, and hydroxyl
radicals, rather than undergoing complete reduction
to water in the electron transport chain. There is thus
a total production of some 1.5 mol of reactive oxygen
species daily, potentially capable of causing damage to
membrane lipids, proteins, and nucleic acids.

Ribofl avin defi ciency

Although ribofl avin is involved in all areas of metabo-
lism, and defi ciency is widespread on a global scale,
defi ciency is not fatal. There seem to be two reasons
for this. One is that, although defi ciency is common,
the vitamin is widespread in foods and most diets will
provide minimally adequate amounts to permit main-
tenance of central metabolic pathways. The second,
more important, reason is that in defi ciency there is
extremely effi cient reutilization of the ribofl avin that
is released by the turnover of fl avoproteins, so that
only a very small amount is metabolized or excreted.
Ribofl avin defi ciency is characterized by lesions of
the margin of the lips (cheilosis) and corners of the

mouth (angular stomatitis), a painful desquamation

of the tongue, so that it is red, dry, and atrophic

(magenta tongue), and a seborrheic dermatitis, with

fi liform excrescences, affecting especially the nasola-

bial folds, eyelids, and ears.

There may also be conjunctivitis with vasculariza-

tion of the cornea and opacity of the lens. This last is

the only lesion of aribofl avinosis for which the bio-

chemical basis is known: glutathione is important in

maintaining the normal clarity of crystallin in the

lens, and glutathione reductase is a fl avoprotein that

is particularly sensitive to ribofl avin depletion.

The main metabolic effect of ribofl avin defi ciency

is on lipid metabolism. Ribofl avin-defi cient animals

have a lower metabolic rate than controls and require

a 15–20% higher food intake to maintain body weight.

Feeding a high-fat diet leads to more marked impair-

ment of growth and a higher requirement for ribofl a-

vin to restore growth.

Resistance to malaria in ribofl avin defi ciency

Several studies have noted that in areas where malaria

is endemic, ribofl avin-defi cient subjects are relatively

resistant and have a lower parasite burden than ade-

quately nourished subjects. The biochemical basis of

this resistance to malaria in ribofl avin defi ciency is

not known, but two possible mechanisms have been

proposed.

● The malarial parasites may have a particularly high

requirement for ribofl avin. Some fl avin analogues

have antimalarial action.

● As a result of impaired antioxidant activity in

erythrocytes, there may be increased fragility of

erythrocyte membranes or reduced membrane fl u-

idity. As in sickle cell trait, which also protects

against malaria, this may result in exposure of the

parasites to the host’s immune system at a vulner-

able stage in their development, resulting in the

production of protective antibodies.

Ribofl avin requirements

Estimates of ribofl avin requirements are based on

depletion/repletion studies to determine the minimum

intake at which there is signifi cant excretion of the

vitamin. In defi ciency there is virtually no excretion

of the vitamin; as requirements are met, so any excess

is excreted in the urine. On this basis the minimum

adult requirement for ribofl avin is 0.5–0.8 mg/day.