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OCR for page 47
Niacin
The biochemical function of nicotinic acid was discov-
ered before the nutritional role of this compound was
appreciated. Warburg et al. (1935) isolated nicotinic
acid from their "old yellow enzyme," subsequently
identified as NADP (nicotinamide-adenine dinucleotide
phosphate), and showed that it was part of a cellular
hydrogen transport system (Warburg and Christian,
19361. Funk (1911) had previously isolated the com-
pound in his search for the antipolyneuritis factor for the
chick. After finding that nicotinic acid was not active in
this animal model of beriberi, Funk dismissed it as being
of little nutritional importance. It was not until Elveh-
jem et al. (1938) identified nicotinic acid as the factor
that prevented "black tongue disease" in dogs that the
nutritional role of the compound was recognized. Spies
et al. (1938) soon demonstrated the importance of nico-
tinic acid in human health by showing that it cured pel-
lagra.
NUTRITIONAL ROLE
Die tally Requirements of Various Species
Niacin is essential in the diets of nonruminant species
for the prevention of a variety of severe metabolic disor-
ders of the skin, gastrointestinal tract, and other organs.
The first signs of niacin deficiency in most species are
loss of appetite, reduced growth, generalized muscular
weakness, digestive disorders, and diarrhea. A scaly
dermatitis and, often, a microcytic anemia follow these
signs. These conditions are referred to as black tongue
disease in dogs, pellagra in humans, and pig pellagra in
swine. The niacin-deficient chick also shows an abnor-
mality of leg development called perosis. The niacin
requirements of animals range from about 11 mg/kg of
diet for dogs to 45 mg/kg of diet for cats. A primary
determinant of this variation is in the efficiency of meta-
bolic conversion of tryptophan to niacin. Ruminants are
usually capable of deriving all of their required niacin
from ruminal microbial synthesis. Microbial synthesis
is via the quinolinic acid pathway as well as from trypto-
phan.
Biochemical Functions
The biochemical bases for the diverse effects of niacin
deficiency involve the numerous metabolic reactions,
which in turn involve nicotinamide. These include some
35 oxidation-reduction reactions in which nicotinamide
participates as either of the pyridine nucleotides
(NADtH] or NADPtH]) acting as two-electron trans-
porters. NADH transfers electrons from metabolic in-
termediates to the mitochondrial electron transport
chain, while NADH and NADPH serve as reducing
agents in a large number of biosynthetic processes.
Thus, nicotinamide has physiologically critical roles in
mitochondrial respiration and in the metabolism of car-
bohydrates, lipids, and amino acids.
FORMS OF THE VITAMIN
Niacin is the accepted term used as the generic de-
scriptor of pyridine 3-carboxylic acids and their deriva-
tives that exhibit the biological activity of the amicle of
nicotinic acid-in other words, nicotinamide. Of the
compounds with niacin activity, nicotinic acid and ni-
cotinamide show the greatest biological potency (see
Figure 11~. Some analogs such as 3-acetyl pyricline and
pyridine 3-sulfonic acid show niacin-antagonistic activi-
ties. Niacin is widely distributed in foods of either plant
or animal origin. Cereals comprise the most important
sources of niacin in most animal diets. Much of that
niacin appears to be present in bound forms with limited
47
OCR for page 48
48 Vitamin Tolerance of Animals
o
11
'':
OCR for page 49
Niacin 49
flushing in humans is probably around 250 mg of nico-
tinic acid (Horrobin, 1980~. The stimulation in produc-
tion of a prostaglandin may produce the skin flush,
which is indicated by the findings that the reaction in
humans is reduced by pretreatment with indomethacin,
an inhibitor of prostaglandin synthetase. In addition,
flushing also can be produced in humans by administra-
tion of either cyclic-AMP or prostaglandin En (Anders-
son et al., 1977; Svedmyr et al., 1977~.
High intake levels (more than 3 g/day) of nicotinic acid
have been shown to affect serum cholesterol and lipo-
protein levels in humans. Although such treatment
reduces levels of very-low-density (VLDL), inter-
mediate-density (IDL), and low-density (LDL) lipopro-
teins, it increases levels of high-density (HDL) lipopro-
teins. The basis of the latter effect appears to be
reduction of HDL catabolism (Blum et al., 19771. For
this reason, nicotinic acid has been used in the treatment
of hyperlipidemias (Patsch et al., 1977; Smith, 1981~.
Side effects of high levels of treatment, such as 300 mg
of nicotinic acid/kg of BW/day for 3 weeks, have been
observed in the normocholesterolemic rat. These in-
clude rebounds in plasma-free fatty acids and triglycer-
ides, and triglyceride accumulation in liver (Subissi et
al., 19801. Although the hypolipidemic effect of ni-
cotinamide appears to be much less than that of nicotinic
acid, studies in rats (Dalton et al., 1970) have shown that
because of the much longer serum half-life of ni-
cotinamide, its hypolipidemic effect is much longer.
The intake of 1 g or more of nicotinic acid has been
found to reduce the urinary clearance of uric acid
(Gershon and Fox, 1974~. This effect is thought to be
involved in the hyperuricemia frequently observed dur-
ing the administration of 3 g/day of nicotinic acid for
treatment of schizophrenia in humans (Hankes, 19841.
Studies on experimental animals have shown that the
animal's exposure to high levels of nicotinamide can
affect the metabolism of xenobiotic agents. Kamat et al.
(1980) showed that the intraperitoneal administration of
100 mg nicotinamide/kg of BW in rats was effective in
inducing the hepatic microsomal mixed function oxy-
genase (MFO) system (namely, NADPH-cytochrome c
reductase, cytochrome P-450, and cytochrome b5), and
several drug-metabolizing enzyme systems (including
aryl hydrocarbon hydroxylase, aminopyrine N-
demethylase, and uridine 5'-diphosphate (UDP) glu-
curonosyl transferase). It is likely that the following
may relate to the altered metabolism of the active
agents by the effect of nicotinamide on the MFO sys-
tem: potentiation of anti-epileptic activity of phenobar-
bital (Bourgeois et al., 19831; prevention of organophos-
phate-induced micromelia in the embryonic chick
(Byrne and Kitos, 1983~; protection from some acute
effects of certain hepatocarcinogens (Schoental, 19771;
reduction of tumorigenesis induced by bracken fern
(Pamukuo et al., 1981) or diethylnitrosamine (Schoen-
tal,19771; and protection from pancreatic islet cell dam-
age due to the diabetigenic substance streptozotocin
(Wilander and Gunnarsson, 1975; Wick et al., 1977; Ka-
zumi et al., 1978; Yoshino et al., 1979~. Most of these
effects have been observed in animals treated with nic-
otinamide at levels of 250 to 500 mg/kg of BW or fed the
vitamin at 0.5 percent of the diet.
Chen et al. (1938) reported the toxicity of nicotinic
acid for dogs. They found that repeated oral administra-
tion of 2 g/day of nicotinic acid (133 to 145 mg/kg of BW)
produced bloody feces in a few dogs. Convulsions and
death followed. Doses of nicotinic acid as great as 0.5 g/
day, which is about 36 mg/kg of BW, produced slight
proteinuria after 8 weeks. Hoffer (1969) has presented
the median lethal doses of nicotinamide in g/kg of BW
for several species. For the mouse, the median lethal
doses are 4.5 to 7 g orally, 2.5 to 4.5 g intravenously! and
2.8 g by subcutaneous injection; for the rat, 5 to 7 g
orally and 4 to 5 g intravenously; and for the rabbis, 2.5 g
intravenously. However, there have been very few ani-
mal studies upon which to base estimates of the toxicity
of high doses of niacin. Studies by Toth (1983) indicated
that life-long exposures of mice to high levels of nic-
otinamide were not carcinogenic. Baker et al. (1976)
showed that dietary levels of nicotinamide above 5,000
mg/kg depressed the growth of chicks, but that dietary
levels of nicotinic acid as great as 20,000 mg/kg did not
affect growth. Certain derivatives of niacin, such as
6-aminonicotinamide, isonicotinic acid, and isonicotinic
hydrazide, have been shown to be lethal, teratogenic,
and/or carcinogenic (Matschke and Fagerstone, 1977;
Tsarichenko et al., 1977; Zackheim, 1978; Uyeki et al.,
1982; Toth,1983~. The local toxicity of 6-aminonicotina-
mide is the basis of its therapeutic use for psoriasis
(Zackheim, 1978~.
PRESUMED UPPER SAFE LEVELS
Estimates of maximum tolerable levels of niacin-
active compounds are not possible because of the lim-
ited definitive quantitative data presently available.
That evidence suggests that levels greater than approx-
imately 350 to 500 mg of nicotinic acid equivalents/kg of
BW/day may be toxic. Because nicotinic acid is well
absorbed, limits of safe exposure of niacin-active com-
pounds are expected to be similar for oral and parenteral
administration. The level of 350 mg nicotinamide/kg of
BW/day is presumed safe for chronic exposure. Nico-
tinic acid may be tolerated at intakes as great as four
times this level.
OCR for page 50
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OCR for page 52
52 Vitamin Tolerance of Animals
SUMMARY
1. Niacin is the generic description for compounds
required by all animals for the metabolic production of
essential metabolic electron carriers NAD(H) and
NADP(H).
2. Limited research indicates that nicotinic acid and
nicotinamide are toxic at dietary intakes greater than
about 350 mg/kg of BW/day.
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