Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

IV. Water-Soluble Vitamins
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ability to metabolize fatty acids (carnitine synthesis) contribute
signs of scurvy.
To maintain these functions, most animals generate
10 to 60 mg of ascorbic acid per 1000 kcal utilized in
the course of normal metabolism. Similarly, requirements
for ascorbic acid, when required in the diet, range from
50 to 250 mg per kilogram of diet (i.e., about 50 mgs per
1000 kcal), which correspond to the amount in mammalian
milk ( Rucker and Steinberg, 2002 ). It is noteworthy
that when fed in excess of metabolic need, tissue levels of
ascorbic acid are homeostatically maintained. Homeostasis
occurs by the induction of ascorbic acid decarboxylases
and cleavage enzymatic activity, which results in CO 2 plus
ribulose or oxalic acid plus threonic acid. These conversions
are probably to protect cells against nonspecific and
oxidative reactions resulting from excesses of reduced metals,
such as iron and copper ( Johnston et al., 2007 ).
2 . Niacin
a . Introduction
Through the elegant work of Goldberger and others, pellagra
was identified as a nutritional deficiency in the 1900s. Commonly
known as the “ disease of the four D’s—dermatitis,
diarrhea, dementia, and death ”—it was first recognized in
Spain and Italy as a specific disease in the late 1700s, as mal
de la Rosa and pellagra, respectively, from pelle (skin) and
agra (rough). In 1810, another Italian, Giovanni Battista
Marzari, proposed that the disease was caused by overreliance
on corn as the main dietary staple. Indeed, there were
two schools of thought: the Zeists , who supported the corn
theory, and the anti-Zeists , who discredited it ( Goldblith and
Joslyn, 1964 ). Niacin deficiency comes about when foodstuffs
(e.g., corn ) are consumed that are low in bioavailable niacin
and the amino acid tryptophan. Tryptophan is important to
niacin status ( Bender, 1996 ), because niacin can be generated
upon tryptophan degradation ( Fig. 23-15 ). Although
niacin deficiency is observed infrequently in free-ranging
animals, it nevertheless is a good example of a vitaminrelated
disease that occurs from consuming a monotonous
diet. In this regard, dogs played an important role as models
for pellagra, as they exhibited a condition called “ black
tongue, ” when given a diet similar to that which produces
pellagra in humans. Black tongue is characterized by initial
reddening of the mucosa of the lips and mouth that
progresses to necrosis of the mucosa accompanied by ropy
saliva, a fetid odor, and diarrhea. In 1937, Elvehjem discovered
that dogs with “ black tongue ” responded dramatically
both to nicotinic acid and to nicotinamide, which was isolated
from liver extracts that had previously been found to
have relatively high antipellagra activity. The acid and the
amide were tested with human pellagrins and gave relief
of the irritation of the mucous membrane of the mouth and
digestive tract and the disappearance of acute mental symptoms
within a few days ( Bender, 1996 ; Kirkland, 2007 ).
With regard to pellagra and corn, niacin is not highly
bioavailable unless the corn is finely ground or processed
under alkaline conditions (e.g., ground in the presence of
limestone). In human populations, this was not the practice
in Western Europe and the southern United States,
although it was the practice in Central and South America.
Normally, niacin is derived from food by hydrolysis of
nicotinamide adenosyl dinucleotide (NAD) and nicotinamide
adenosyl phosphodinucleotide (NADP) to niacin by
the action of pancreatic or intestinal nucleosides and phosphatases.
Facilitating NAD and NADP hydrolysis by alkali
treatment of corn or increasing surface area is important
to increasing the bioavailability of niacin. Given that most
animals consume diets that contain adequate tryptophan,
and available NAD and NADP, niacin deficiency is usually
not a problem. An exception to this generalization is
cats. In this species, the degradation of tryptophan does not
proceed along a pathway that leads to nicotinic acid, even
though all the enzymes for the pathway are present. High
activity of the enzyme picolinic carboxylase, at a branch
point in the pathway, results in diversion from eventual
NAD production. For cats and probably all other felids,
available niacin is an obligatory dietary factor.
b . Functions
NAD and its phosphorylated form, NADP, are two coenzymes
derived from niacin ( Fig. 23-15 ). Both contain an unsubstituted
pyridine 3-carboxamide that is essential to function
in redox reactions with a chemical potential near 0.32 V.
Virtually all cells are capable of converting niacin to NAD
( Kirkland, 2007 ). Most enzymes requiring NAD are oxidoreductases
(dehydrogenases) that aid the catalysis of a diverse
array of reactions, such as the conversion of alcohols and
polyols to aldehydes or ketones. The most common mechanisms
involve the stereospecific abstraction of a hydride ion
(H:) from the substrate with subsequent transfer. Further,
cells utilize NAD in catabolic pathways, whereas NADP is
utilized in synthetic pathways. An additional and equally
important function of NAD is its role as a substrate in polyand
monoribosylation reactions. Mono- and polyribosylations
are important to many cellular regulatory functions. Enzymes
that undergo monoribosylation can become activated or deactivated
upon addition of ADP-ribose. Somewhat analogous to
phosphorylation, ribosylation represents another example of
covalent modification as a regulatory control.
In the nuclei of cells, polyribosylation of histone precedes
the normal process of DNA repair (Hageman and
Stierum, 2001). This later phenomenon is important in
that pellagra-related lesions often involve the skin, following
exposure to UV light. UV damage of epidermal cell
DNA is an underlying mechanism for the dark pigmented
lesions associated with pellagra. Lack of niacin and therefore
NAD is thought to be a contributing factor to the skin
lesions because of the inability of cells to carry out polyribosylation
reactions. It is this nonredox function of NAD