Chemically, niacin is one of the simplest vitamins, having the empirical formula C6H3O2N (Illus. 13-1). Nicotinic acid and nicotinamide correspond to 3-pyridine carboxylic acid and its amide, respectively. There are antivitamins or antagonists for niacin. These compounds have the basic pyridine structure; two of the important antagonists of nicotinic acid are 3-acetyl pyridine and pyridine sulfonic acid. Nicotinic acid and nicotinamide (niacinamide) generally possess the same activity, although one report with lactating cows suggested that the nicotinamide form has slightly higher activity (Jaster and Ward, 1990). Nicotinic acid is converted to the amide form in the tissues, and Erickson et al. (1991) suggests this occurs in the rumen. Nicotinamide functions as a component of two coenzymes: nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP).
Both nicotinic acid and nicotinamide are white, odorless, crystalline solids soluble in water and alcohol. They are very resistant to heat, air, light and alkali and thus are stable in feeds. Niacin is also stable in the presence of the usual oxidizing agents. However, it will undergo decarboxylation at a high temperature, when in an alkaline medium. An important source of niacin for ruminants is ruminal synthesis. Synthesis of niacin in the rumen has been demonstrated in sheep (Rérat et al., 1959), cattle (Hungate, 1966) and goats (Porter, 1961). This synthesis also has been suggested to be under metabolic control; e.g., more is synthesized when small amounts are provided in the ration and vice versa (Porter, 1961; Abdouli and Schaefer, 1986). Nicotinic acid and its amide are readily and very efficiently absorbed by diffusion at either physiological or pharmacologic doses. The mechanism by which nicotinamide nucleotides present in animal feeds are absorbed, however, is unknown. Whether the coenzyme is hydrolyzed in the lumen or after it is taken up by the mucosa is unclear.
Nicotinic acid and nicotinamide are rapidly absorbed from the stomach and the intestine (Nabokina et al., 2005; Jacob, 2006). Absorption from the small intestine seems to be the major route by which niacin is made available to the host. Although direct absorption from the rumen is possible, normally it is thought to be limited because only a small portion (3% to 7%) of the vitamin is in the supernatant fraction of rumen fluid; most is bound within the microbes themselves (Rérat et al., 1959).
Niacin in foods occurs mostly in its coenzyme forms, which are hydrolyzed during digestion, yielding nicotinamide, which seems to be absorbed as such without further hydrolysis in the gastrointestinal tract. The intestinal mucosa is rich in niacin conversion enzymes such as NAD glycohydrolase (Henderson and Gross, 1979). Nicotinamide is released from NAD in the liver and intestines by glycohydrolases for transport to tissues that synthesize NAD as needed. In the gut mucosa, nicotinic acid is converted to nicotinamide (Stein et al., 1994). Nicotinamide is the primary circulating form of the vitamin and is converted into its coenzyme forms in the tissues. Blood transport of niacin is associated mainly with red blood cells. Niacin rapidly leaves the blood stream and enters kidney, liver and adipose tissues.
The tissue content of niacin and its analogs, NAD and NADP, is a variable factor, dependent on the diet and a number of other factors, such as strain, sex, age and treatment of animals (Hankes, 1984). Although niacin coenzymes are widely distributed in the body, no true storage occurs. The liver is the site of greatest niacin concentration in the body, but the amount stored is minimal.
Urine is the primary pathway of excretion of absorbed niacin and its metabolites. The principal excretory products in humans, dogs, rats, and pigs are methylated metabolite N1-methylnicotinamide or as two oxidation products of this compound, 4-pyridone or 6-pyridone of N1-methylnicotinamide. On the other hand, in herbivores, niacin does not seem to be metabolized by methylation, but large amounts are excreted unchanged. In the chicken, however, nicotinic acid is conjugated with ornithine as either alpha- or delta-nicotinyl ornithine or dinicotinyl ornithine. The measurement of the excretion of these metabolites is carried out in studies of niacin requirements and niacin metabolism.
The amino acid tryptophan is a precursor for the synthesis of niacin in the body. There is considerable evidence that synthesis can occur in the intestine. There is also evidence that synthesis can take place elsewhere within the body. The extent to which the metabolic requirement for niacin can be met from tryptophan will depend first on the amount of tryptophan in the diet and second on the efficiency of conversion of tryptophan to niacin. The pathway of tryptophan conversion to nicotinic acid mononucleotide in the body is shown in Figure 13-1. Protein, energy, vitamin B6 and riboflavin nutritional status and hormones affect one or more steps in the conversion sequence shown in Figure 13-1, and hence can influence the yield of niacin from tryptophan. Iron is required by two enzymes for the conversion of tryptophan to niacin with a deficiency reducing tryptophan utilization. At low levels of tryptophan intake, conversion efficiency is high. It decreases when niacin and tryptophan levels in the diet are increased.
Conversion of tryptophan to niacin is probably due to inherent differences in liver levels of picolinic acid carboxylase, the enzyme that diverts one of the intermediates (2-amino, 3-acroleylfumaric acid) to the picolinic acid pathway instead of allowing this compound to condense to quinolinic acid, the immediate precursor of nicotinic acid. Picolinic acid carboxylase activity in livers of various species has a positive correlation to experimentally determined niacin requirements. The rat diverts very little of its dietary tryptophan to carbon dioxide and water, and thus is relatively efficient in converting tryptophan to niacin. Picolinic acid carboxylase activity of various species is presented in Table 13-1.
The cat has been shown to have 30 to 50 times as much picolinic acid carboxylase activity as the rat. Thus, the cat has so much of this enzyme that it cannot convert any of its dietary tryptophan to niacin. The cat, therefore, has an absolute requirement for niacin itself. The duck has a very high niacin requirement (approximately twice as high as chickens), with considerably higher levels of picolinic acid carboxylase activity (Scott et al., 1982).
The major function of niacin is in the coenzyme forms of nicotinamide, NAD and NADP. Enzymes containing NAD and NADP are important links in a series of reactions associated with carbohydrate, protein and lipid metabolism. They are especially important in the metabolic reactions that furnish energy to the animal. The coenzymes act as an intermediate in most of the H+ transfers in metabolism, including more than 200 reactions in the metabolism of carbohydrates, fatty acids and amino acids. These reactions are of paramount importance for normal tissue integrity, particularly for the skin, the gastrointestinal tract and the nervous system. Like the riboflavin coenzymes, the NAD- and NADP-containing enzyme systems play an important role in biological oxidation-reduction systems due to their capacity to serve as hydrogen-transfer agents. Hydrogen is effectively transferred from the oxidizable substrate to oxygen through a series of graded enzymatic hydrogen transfers. Nicotinamide-containing enzyme systems constitute one such group of hydrogen transfer agents. Important metabolic reactions catalyzed by NAD and NADP are summarized as follows (McDowell, 2000; Kirkland, 2007):
a. Carbohydrate metabolism:
b. Lipid metabolism:
c. Protein metabolism:
e. Rhodopsin synthesis
Niacin, riboflavin and co-enzyme Q10 are associated with poly (ADP-ribose) which is involved in the post-translational modification of nuclear proteins. The poly ADP-ribosylated proteins seem to function in DNA repair, DNA replication and cell differentiation (Carson et al., 1987; Premkumar et al., 2008). Poly (ADP-ribose) is synthesized in response to DNA strand breaks. Rat data have shown that even a mild niacin deficiency decreases liver poly (ADP-ribose) concentrations and that poly (ADP-ribose) levels are also altered by food restriction (Rawling et al., 1994). Zhang et al. (1993) suggest that a severe niacin deficiency may increase the susceptibility of DNA to oxidative damage, likely due to the lower availability of NAD. Turnover rates of protein in Japanese quail have been related to niacin deficiency; a high turnover rate due to the deficiency was primarily attributed to enhanced degradation rate of proteins rather than enhanced synthesis rate of proteins (Park et al., 1991).
For ruminants, niacin is particularly required for unique features involving protein and energy metabolism, including liver detoxification of portal blood NH3 to urea and liver metabolism of ketones in ketosis. It is apparent that niacin can increase microbial protein synthesis (Girard, 1998). It may result in an increased molar proportion of propionate in rumen volatile fatty acids and may cause an increased rate of flow of material through the rumen. The primary function of interest for lactating dairy cows deals with the role of niacin in fatty acid oxidation and glucose synthesis, particularly as a preventive and possible treatment for clinical and subclinical ketosis.
Wide variations in niacin requirements have been reported. Cunha (1982) lists a number of factors that influence niacin requirements: (1) genetic differences that can influence niacin needs; (2) selection for poultry with increased production levels; (3) the ability to synthesize niacin from tryptophan; (4) increased stress and subclinical disease level on the farm because of closer and more frequent contact between poultry in confinement; (5) trend toward more intensified operations, which may lessen opportunity for coprophagy; (6) newer methods of handling and processing feeds, which may affect niacin and tryptophan level and availability; (7) various nutrient interrelationships including amino acid imbalances; and (8) molds and antimetabolites in feeds that can increase certain niacin and tryptophan needs. Blair (1993) also suggests that increased stress associated with intensive production practices and disease influences niacin requirements. Rapidly growing broiler chicks require more niacin because of the faster gains of modern strains of birds as compared with more historical populations. Animal species differ widely in ability to synthesize niacin from tryptophan. From a variety of experiments, approximately 60 mg of tryptophan is estimated to be equivalent to 1 mg of niacin in humans, while the rat is more efficient at a conversion rate of 35 to 50 mg of tryptophan required. Baker et al. (1973) suggested a conversion factor of 45 mg of tryptophan to 1 mg niacin in the young chick. Conversion efficiency is probably due to inherent differences in liver levels of picolinic acid carboxylase, the enzyme that diverts one of the intermediates (2-amino, 2-acroleylfumaric acid) toward the glutaryl-CoA pathway instead of allowing this compound to condense to quinolinic acid, the immediate precursor of nicotinic acid. Picolinic acid carboxylase in livers of various species has a very close inverse relationship to experimentally determined niacin requirements. Iron deficiency reduced tryptophan utilization for niacin synthesis (Oduho et al., 1994). For chickens, tryptophan conversion to niacin activity during an iron deficiency was a ratio of 56:1, but with an iron-adequate diet, 42:1.Chicks have a conversion ratio of tryptophan:nicotinic ratio of 45:1 to 50:1 (Baker et al., 1973), while turkeys, with higher levels of picolinic acid, have conversion rates of 103:1 to 119:1 (Ruiz and Harms, 1988). The duck has a very high niacin requirement (approximately twice as high as chickens), with considerably higher levels of picolinic acid carboxylase activity (Scott et al., 1982). Chen et al. (1996) recently compared efficiency of conversion of tryptophan:nicotinic acid between ducklings and chicks. The results indicated tryptophan to nicotinic acid ratios of 181:1 for Peking ducklings, 172:1 for Mule ducklings and 47:1 for broiler chicks. Liver picolinic acid carboxylase (PAC) activity was four to five times higher in ducklings than in chickens. Different strains of chickens have different niacin requirements (McDowell, 2000). A chicken strain that requires a high amount of niacin has a higher level of liver picolinic acid carboxylase activity than a strain with a low niacin requirement.
The NRC (1994) recommends from 10 to 65 mg of niacin per kg (4.5 to 29.5 mg per lb) of feed for various classes of poultry. For turkeys, the requirement is quite wide, varying from 40 to 60 mg per kg (18.2 to 27.3 mg per lb). Harms et al. (1988) reported that 23.6 mg per kg (10.7 mg per lb) of niacin from a corn-soybean diet was sufficient for maximum egg production and hatchability in turkeys. However, body and egg weights were significantly increased when 8.4 and 16.7 mg per kg (3.8 and 7.5 mg per lb) of niacin were added to the diet, respectively. Wen-Jie et al. (1995) suggested that 60 mg per kg (27.3 mg per lb) of niacin would be adequate for broiler chickens fed on a diet containing 0.25% tryptophan and 28.3 mg per kg (12.9 mg per lb), niacin respectively, from hatching to four weeks old, and 0.22% tryptophan and 25.8 mg per kg (11.7 mg per lb) niacin at five to seven weeks old. In another study with broilers, the niacin requirement was determined to be 80 mg per kg (36.4 mg per lb) feed (Whitehead, 2000).
Niacin is widely distributed in feedstuffs of both plant and animal origin. Animal and fish by-products, distiller’s grains and yeast, various distillation and fermentation solubles and certain oilseed meals are good sources. The niacin in cereal grains and their by-products is in a bound form, which is largely unavailable at least to monogastric animals (Luce et al., 1966; 1967). Two types of bound niacin were initially described: (1) a peptide with molecular weight of 12,000 to 13,000, the so-called niacinogens, and (2) a carbohydrate complex with a molecular weight of approximately 2,370 (Darby et al., 1975). The name niacytin has been used to designate this latter material from wheat bran. Ghoshet al. (1963), using a microbiological assay, reported that 85% to 90% of the total nicotinic acid in cereals is in a bound form. Oilseeds contain about 40% of their total niacin in bound form, while only a small proportion of the niacin in pulses, yeast, crustacean, fish, animal tissue, or milk is bound. By use of a rat assay procedure, for eight samples of mature cooked cereals (corn, wheat, rice and milo), only about 35% of the total niacin was available (Carter and Carpenter, 1982). It seems likely that much of this niacin will also be unavailable to rumen microorganisms. Any dietary niacin escaping degradation in the rumen will likely also be unavailable for absorption in the lower gut.
In the calculation of the niacin content of formulated diets, probably all the niacin from cereal grain sources should be ignored or at least given a value no greater than one-third of the total niacin. Some bound forms of niacin are biologically available, but the niacin in corn is particularly unavailable and is implicated in the etiology of pellagra in societies that consume large quantities of the grain. The bioavailability of niacin is 100% in soybean meal but zero in wheat and sorghum and varies from 0% to 30% in corn (McDowell and Ward, 2008).
In immature seeds, niacin occurs as part of biologically available coenzymes necessary for seed metabolism. Binding of niacin to carbohydrates by ester linkages may cause it to be retained in the mature seed until it is utilized; the vitamin availability for man and animal is thus impaired. In rat growth assays for available niacin, corn harvested immaturely (“milk stage”) gave values from 74 to 88 µg per gm, whereas corn harvested at maturity gave assay values of 16 to 18 µg per gm (Carpenter et al., 1988).
Most species can use the essential amino acid tryptophan from which niacin can be synthesized. Because tryptophan can give rise to body niacin, both the niacin and tryptophan content should be considered together in expressing niacin values of feeds. However, tryptophan is preferably used for protein synthesis (Kodicek et al., 1974). Consequently, it is unlikely that tryptophan conversion greatly contributes to the niacin supply, since feedstuffs used in most diets tend to be low in tryptophan. Furthermore, the efficiency of the biochemical conversion is low; with cattle, it is less efficient than with the pig and chicken (Scott et al., 1982).
Niacin is commercially available in two forms, niacinamide and nicotinic acid, with both forms providing about the same niacin biological activity. However, a recent report showed the niacinamide significantly increased (P < 0.05) in milk, milk fat and 4% fat-corrected milk over controls during lactation. These production parameters were also higher compared to nicotinic acid- supplemented animals, but not significantly (P < 0.05) (Jaster and Ward, 1990). An additional source of supplemental niacin would be from the vitamin K supplement menadione nicotinamide bisulfite (MNB). Results with chicks suggest MNB is fully effective as a source of vitamin K and niacin activity (Oduho et al., 1993).
A deficiency of niacin is characterized by severe metabolic disorders in the skin and digestive organs. The first signs to appear are loss of appetite, retarded growth, weakness, digestive disorders and diarrhea (Illus. 13-2). The deficiency is found in both human and animal populations that are overly dependent on foods (particularly corn) low in available niacin and its precursor tryptophan. There is good evidence that poultry—even chick and turkey embryos—are able to synthesize niacin, but the rate of synthesis may be too slow for optimal growth.
Courtesy of University of Wisconsin
Ruiz and Harms (1987) reported that broilers from three to seven weeks of age did not respond in terms of growth or feed utilization to niacin addition in a corn-soybean meal diet. Harms and Bootwalla (1992a) also concluded that White Leghorn pullets zero to six weeks of age consuming a corn-soybean meal diet do not respond to niacin. However, supplemental niacin is required for broilers from one to 21 days of age (Ruiz and Harms, 1990a, b). It has been claimed that before there can be a marked deficiency of niacin in the chicken, there must first be a deficiency of tryptophan. Chicks at hatch have considerable tryptophan contained in the protein of the yolk, thus a niacin deficiency will not readily occur unless the feed is low for both the amino acid and the vitamin (NRC, 1994). Experiments using diets containing a limited amount of tryptophan have shown that the chick does require niacin and that a deficiency produces an enlargement of the tibiotarsal joint, a bowing of the legs, poor feathering, and a dermatitis (Illus. 13-3) on the feet and head (Scott et al., 1982). Oloyo (1997) noted that supplementing a niacin-deficient broiler diet with 15.0 mg of niacin per kg (6.8 mg per lb) prevented dermatitis, but 22.5 mg of niacin per kg (10.1 mg per lb) was required to prevent leg deformities. The main clinical sign of niacin deficiency in young chicks is an enlargement of the hock joint and bowing of the legs similar to perosis (Illus. 13-4). The main difference between this condition and the perosis of manganese or choline deficiency is that in niacin deficiency the Achilles’ tendon rarely slips from its condyles.
Niacin deficiency in the chick is characterized by appetite loss and growth failure. The deficiency results in “black tongue,” a condition characterized by inflammation of the tongue and mouth cavity. Beginning at about two weeks of age, the entire mouth cavity, as well as the esophagus, becomes distinctly inflamed, growth is retarded, and feed consumption is reduced. There is weight loss and both egg production and hatchability are reduced in niacin deficient laying hens. Shell quality is improved with niacin supplementation (Leeson et al., 1991). Death loss can be affected. Jackson (1992) reported that 30 mg per kg (13.6 mg per lb) of dietary niacin significantly decreased mortality of layers, when compared to 10 mg per kg (4.5 mg per lb).
Turkey poults, pheasant chicks, ducklings and goslings all expressed perosis (Illus. 13-5) as the primary niacin deficiency sign (NRC, 1994). Signs of niacin deficiency in turkeys and ducks, while similar to those in chickens, are much more severe. Compared to the chick, the turkey poult, duckling, pheasant chick and gosling have higher requirements for niacin. This higher requirement is related to the less efficient conversion of tryptophan to niacin by these species. Ducks receiving low-niacin diets show severely bowed legs and ultimately become so crippled and weak that they cannot walk. Niacin deficiency in the turkey is also characterized by a severe bowing of the legs and enlargement of the hock joint. Goslings on purified diets developed perosis and hock deformities that were prevented with nicotinic acid administration (Briggs et al., 1953).
Courtesy of N. Ruiz and R. Harms, University of Florida
Niacin supplementation must be considered as a possibility with all classes of animals and in particular with poultry diets. Much of niacin in common feeds (plant sources) are in a bound form that is not available to animals. In formulating poultry diets, therefore, niacin values for corn and other cereal grains and their by-product feeds should be largely disregarded. It is best to assume that these feeds provide no available niacin for the chick or pig (Cunha, 1982). The chick and most species can use the essential amino acid tryptophan to synthesize niacin, but they cannot convert niacin back to tryptophan. Therefore, if a diet contains enough niacin, the tryptophan is not depleted for niacin synthesis. Most poultry diets do not contain large excesses of tryptophan, particularly diets based on corn. Tryptophan concentrations are not only low in corn, but largely unavailable. Therefore, one should ensure that poultry diets are adequate in niacin since, as it is inexpensive, it would be poor economics to satisfy niacin needs by the more expensive tryptophan (Cunha, 1982). The most critical time for supplementation is during early growth when requirements are the highest. Niacin requirements as recommended by NRC (1994) for poultry may be insufficient. Supplementation of niacin for poultry is important to provide a reasonable safety factor and higher niacin levels are recommended when subclinical disease, stress and higher production rates are expected. Nutritionists must judge their own operation in relation to the type of diet, strain of birds, stress conditions present and other factors which may influence the need by poultry for niacin supplementation. Maurice (1988) reported that, for fast-growing modern turkeys, niacin supplementation of 140 mg per kg (63 mg per lb) of diet in young poults and 50 to 100 mg (23 to 45 mg per lb) for older birds is needed to address the unpredictable and variable factors encountered under commercial production. Niacin is supplied in two forms, niacinamide and nicotinic acid, with both forms providing available niacin. In studies with chicks, relative to nicotinic acid used as a standard (100%), nicotinamide activity was 124%. Nicotinamide in nicotinamide adenine dinucleotide (NAD) was utilized with an efficiency of 95% relative to nicotinamide per se (Oduho and Baker, 1993). Crystalline products are used in feeds and pharmaceuticals, and dry dilutions are used in feeds. An additional source of supplemental niacin would be from the vitamin K supplement menadione nicotinamide bisulfite (MNB). Results with chicks suggest that MNB is fully effective as a source of vitamin K and niacin activity (Oduho et al., 1993).
Commercially produced niacin is quite stable compared to most other vitamins. Synthetic niacin and the amide were found to be stable in premixes with or without minerals for three months (Verbeeck, 1975). Gadient (1986) reports niacin to be insensitive to heat, oxygen, moisture and light. The retention of niacin activity in pelleted feeds after three months at room temperature should be 95% to 100% as a general rule.
Harmful effects of nicotinic acid occur at levels far in excess of requirements. Limited research indicated that nicotinic acid and nicotinamide are toxic at dietary intakes greater than about 350 mg per kg (160 mg per lb) of body weight per day (NRC, 1987). Clinical signs for niacin toxicosis in chicks include reduced egg production, growth retardation, short legs and coarse, dense feathering. High dietary levels of niacin (0.75% to 2.0%) fed to broilers were detrimental to dimensions and mechanical properties of bone (Johnson et al., 1992; 1995; Leeson and Summers, 2001). There was no change in the mineral content of the tibia, but bone strength decreased with increased susceptibility to fracture.
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