The Vitamins 161not clear to what extent urinary excretion of trigonel-
line refl ects endogenous methylation of nicotinic
acid, since there is a signifi cant amount of trigonelline
in foods, which may be absorbed, but cannot be
utilized as a source of niacin, and is excreted
unchanged.
Metabolic functions of niacin
The best-defi ned role of niacin is in the metabolism of
metabolic fuels, as the functional nicotinamide part of
the coenzymes NAD and NADP, which play a major
role in oxidation and reduction reactions. The oxi-
dized coenzymes have a positive charge on the nico-
tinamide ring nitrogen and undergo a two-electron
reduction. The oxidized forms are conventionally
shown as NAD(P)+ and the reduced forms either as
NAD(P)H 2 or, more correctly, as NAD(P)H + H+,
since although it is a two-electron reduction, only one
proton is incorporated into the ring, the other remain-
ing associated with the coenzyme.
In general, NAD+ acts as an electron acceptor in
energy-yielding metabolism, being oxidized by the
mitochondrial electron transport chain, while the
major coenzyme for reductive synthetic reactions is
NADPH. An exception to this general rule is the
pentose phosphate pathway of glucose metabolism,
which results in the reduction of NADP+ to NADPH,
and is the source of half the reductant for fatty acid
synthesis.
In addition to its coenzyme role, NAD is the source
of ADP-ribose for the ADP-ribosylation of a variety
of proteins and poly(ADP-ribosylation) and hence
activation of nucleoproteins involved in the DNA
repair mechanism.
In the nucleus, poly(ADP-ribose)polymerase is
activated by binding to breakage points in DNA. The
enzyme is involved in activation of the DNA repair
mechanism in response to strand breakage caused by
radical attack or UV radiation. In cells that have suf-
fered considerable DNA damage, the activation of
poly (ADP-ribose) polymerase may deplete intracel-
lular NAD to such an extent that ATP formation is
impaired, leading to cell death.
ADP-ribose cyclase catalyzes the formation of
cyclic ADP-ribose from NAD, and of nicotinic acid
adenine dinucleotide phosphate from NADP (by cat-
alyzing the exchange of nicotinamide for nicotinic
acid). Both of these compounds act to raise cytosolic
calcium concentrations by releasing calcium from
intracellular stores, acting as second messengers in
response to nitric oxide, acetylcholine, and other
neurotransmitters.Pellagra: a disease of tryptophan and
niacin defi ciency
Pellagra became common in Europe when maize
was introduced from the New World as a convenient
high-yielding dietary staple, and by the late
nineteenth century it was widespread throughout
southern Europe, north and south Africa, and the
southern USA. The proteins of maize are particularly
lacking in tryptophan, and as with other cereals little
or none of the preformed niacin is biologically
available.
Pellagra is characterized by a photosensitive der-
matitis, like severe sunburn, typically with a butterfl y-
like pattern of distribution over the face, affecting all
parts of the skin that are exposed to sunlight. Similar
skin lesions may also occur in areas not exposed to
sunlight, but subject to pressure, such as the knees,
elbows, wrists, and ankles. Advanced pellagra is also
accompanied by dementia (more correctly a depres-
sive psychosis), and there may be diarrhea. Untreated
pellagra is fatal.
The depressive psychosis is superfi cially similar to
schizophrenia and the organic psychoses, but clini-
cally distinguishable by sudden lucid phases that
alternate with the most fl orid psychiatric signs. It is
probable that these mental symptoms can be explained
by a relative defi cit of the essential amino acid tryp-
tophan, and hence reduced synthesis of the neuro-
transmitter 5-hydroxytryptamine (serotonin), and
not to a defi ciency of niacin per se.Additional factors in the etiology of pellagra
Pellagra also occurs in India among people whose
dietary staple is jowar (Sorghum vulgare), even though
the protein in this cereal contains enough tryptophan
to permit adequate synthesis of NAD. Here the
problem seems to be the relative excess of leucine in
the protein, which can inhibit the synthesis of NAD
from tryptophan. It is likely that leucine is a factor in
the etiology of pellagra only when the dietary intakes
of both tryptophan and niacin are low, a condition
that may occur when sorghum is the dietary staple,
especially at times of food shortage.