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DSM in Animal Nutrition & Health

Niacin

Properties and Metabolism

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).

 

Illustration 13-1

13Illustration_13-1_Niacin

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 is the 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 as well as hormones, affect one or more steps in the conversion sequence shown in Figure 13-1. Therefore, they 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.

 

Figure 13-1: Conversion of Tryptophan to Nicotinic Acid Mononucleotide Plus Some Side Reactions

13Figure_13-1_Conversion_of_Tryptophan_to_Nicotinic_Acid_Mononucleotide

Animal species differ widely in ability to synthesize niacin from tryptophan, but all are relatively inefficient. From a variety of experiments, approximately 60 mg tryptophan is estimated to be equivalent to 1 mg niacin in humans, while the rat is more efficient at a conversion rate of 35 to 50 mg tryptophan required. Conversion efficiency of tryptophan to niacin in the chick is estimated to be 45:1 (Baker et al., 1973; Chen and Austic, 1989) and relatively efficient, whereas in the turkey it is inefficient, with conversions ranging from 103:1 to 119:1 (Ruiz and Harms, 1990). Ruminants would be less efficient in this conversion than most species. 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, 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. The 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).

13Table_13-1_Picolinic_Acid_Carboxylase_Activity_in_Various_Species

Functions

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:

  • 1) Glycolysis (anaerobic and aerobic oxidation of glucose)
  • 2) TCA (Krebs) cycle

b) Lipid metabolism:

  • 1) Glycerol synthesis and breakdown
  • 2) Fatty acid oxidation and synthesis
  • 3) Steroid synthesis

(c) Protein metabolism:

  • 1) Degradation and synthesis of amino acids
  • 2) Oxidation of carbon chains via the TCA cycle

(d) Photosynthesis

(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 this deficiency was primarily attributed to an 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. This includes 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.

 

Requirements

Wide variation in niacin requirements of animals has been reported. This generally occurs because niacin is synthesized from tryptophan and much of dietary niacin is in a bound form unavailable to humans and animals. It is easier to establish the niacin requirement for the cat (also mink and most fish), since they lack the ability to convert tryptophan to niacin. For species like the dog that have the capacity to synthesize niacin from tryptophan, it is impossible to set the niacin requirement unless the tryptophan level is specified and it is known that the diet is adequate in vitamin B6 and riboflavin. Both vitamin B6 and riboflavin are needed in synthesis of niacin from tryptophan. For the dog, niacin conversion from tryptophan is inefficient. It was estimated that 1 g of L-tryptophan is equivalent to about 7.6 mg of niacin in dogs (Singal et al., 1948). Adequate iron is also required by two enzymes for conversion of tryptophan to niacin (Oduho and Baker, 1993). Other factors that may influence niacin requirements for dogs and cats include 1) genetic differences, such as selection for a leaner animal; 2) increased stress and subclinical disease level, as companion animals are in closer or more frequent contact; 3) newer methods of handling and processing feeds that may affect niacin and tryptophan level and availability; 4) various nutrient interrelationships, including amino acid imbalances; and 5) molds and antimetabolites in feeds that can increase certain nutrient needs.The type of carbohydrate consumed may influence niacin requirements. For maximal growth the fish tilapia fingerlings required 26 ppm niacin when fed a glucose diet compared to 121 ppm for those fish fed a dextrin (from corn) diet (Shiau and Suen, 1992).

For dogs and cats, there are no experimental data available to give a requirement for niacin during pregnancy and lactation. However, for humans the rate of conversion of tryptophan to niacin appears to be enhanced in pregnancy due to higher levels of circulating estrogen (Rose and Braidman, 1971; Horwitt et al., 1975). This more efficient conversion may have application to dog niacin requirements.

 

A. Requirements for Dogs

In growing dogs fed a corn-based diet and given intramuscular injections of nicotinic acid on a body weight basis, 340 µg nicotinic acid per kg (154.5 µg per lb) per day prevented appearance of niacin deficiency (black tongue), while 126 µg per kg (57.3 µg per lb) per day produced incipient signs of the disease (Sebrell et al., 1938). The dietary requirement of nicotinic acid (calculated from single-dose feedings) for adult dogs was 200 to 225 µg per kg (90.9 to 102.3 µg per lb) of body weight per day and for growing dogs 250 to 365 µg per kg (113.6 to 165.9 µg per lb) of body weight per day (Schaefer et al., 1942b).For typical dog diets with minimal quantities of tryptophan, the daily requirement of the adult dog will be met by 225 µg niacin per kg (102.3 µg per lb) of body weight and for the growing dog by 450 µg per kg (204.5 µg per lb) of body weight. These amounts will be supplied by diets containing 3 mg of niacin equivalents per 1,000 kcal ME (NRC, 1985). The Association of American Feed Control Officials (AAFCO, 1992) recommends 11.4 mg niacin per kg (5.18 mg per lb) of diet for all classes of dogs. According to the NRC (2006) the niacin requirement for all classes of dogs is 17 mg per kg (7.7 mg per lb) of diet.

 

B. Requirements for Cats

Information on niacin requirements for cats is limited. Because of the inability of the cat to convert tryptophan to niacin, the niacin requirements are higher for cats versus dogs. For growing cats, Braham et al. (1962) found that an oral intake of 5 mg of nicotinic acid per day was adequate as measured by N-methylnicotinamide excretion. In the absence of further information, the minimal requirements of 40 mg niacin per kg (18.2 mg per lb) diet is suggested (NRC, 2006). AAFCO (2007) recommends 60 mg niacin per kg (27.3 mg per lb) of diet for all classes of cats.

 

Sources

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. Ghosh et al. (1963), using a microbiological assay, reported that 85% to 90% of the total niacin is 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 calculations of the niacin content of formulated diets, probably all 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 niacin to carbohydrate 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 g, whereas corn harvested at a maturity gave assay values of 16 to 18 µg per g (Carptenter et al., 1988).

Most species can use the essential amino acid tryptophan and synthesize niacin from it. 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 that niacinamide significantly increased vitamin levels (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 that MNB is fully effective as a source of vitamin K and niacin activity (Oduho et al., 1993).

 

Deficiency

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. The deficiency is found in human and animal populations that are overly dependent on foods, particularly corn, that are low in available niacin and its precursor tryptophan (if the species can synthesize niacin from tryptophan). To date, a functional biochemical test for assessing body reserves is limited. Determination of blood serum levels of niacin or niacin-dependent enzymes has not proved to be a reliable or acceptable method for evaluating niacin status. However, although NAD in liver was not affected in niacin-deficient quail, the level of pectoral muscle NAD was markedly reduced (Park et al., 1991). Measurement of niacin metabolites as a status indicator would be dependent on species, as marked differences in type of metabolites exist among species. For most monogastric species, including dogs and cats, niacin is excreted largely as methylated products. For determining niacin requirements and status, urinary N-methylnicotinamide has been measured in both dogs (NRC, 1985) and cats (Braham et al., 1962). For dogs, urinary excretion of N-methylnicotinamide is decreased, and there are decreased liver and skeletal muscle concentrations of NAD and NADP when there is a niacin deficiency (NRC, 1985).

 

A. Deficiency in Dogs

Historically, a new disease of dogs was reported in the United States and Europe during the late 1800s and early 1900s. In the southern United States, the disease was known as “sore mouth” or “black tongue.” Signs similar to those of the naturally occurring disease could be produced experimentally by using a diet of whole corn, boiled cowpeas, casein, sucrose, cottonseed oil, cod liver oil, salt and calcium carbonate (Goldberger and Wheeler, 1928). The similarity of niacin deficiency signs between dogs and the devastating human disease pellagra in the southern United States was important. The dog became the laboratory animal used to identify the vitamin deficiency. The black tongue (canine pellagra) had naturally occurred in dogs fed a diet primarily of flaked corn (maize) with little material of animal origin. The onset of clinical signs for black tongue was acute, with anorexia and weight loss appearing first. The initial lesions were described as a reddening of the mucosa of the lips and later that of the cheeks and floor of the buccal cavity. Patches of superficial necrosis of these areas occurred, as well as necrosis of the tongue, soft palate, and gums. Accompanying the necrosis was drooling of thick ropy saliva with a fetid odor. The inflammatory changes may extend to the esophagus and eventually to the large intestine. There was bloody diarrhea, inflammation and hemorrhagic necrosis of the duodenum and jejunum with shortening and clubbing of villi, and inflammation and degeneration of the mucosa of the large intestine. Occasionally dogs with canine pellagra exhibited pruritic dermatitis of the hind legs and ventral abdomen (Scott et al., 1995). Uncorrected deficiencies lead to dehydration, emaciation, and death (NRC, 1985). Because of a burning or itching sensation, animals would scratch or bite the skin, producing a traumatic dermatitis. Death generally occurred within 10 days of the onset of clinical signs (Ralston Purina, 1987).

On autopsy, gross lesions of niacin deficiency included emaciation and congested, necrotic buccal mucosa. The rugae of the duodenum and jejunum were moderately atrophic, and in some segments a thick layer of mucus and bile streaked with blood covered the mucous membrane (Madhavan et al., 1968).

 

B. Deficiency in Cats

Cats deficient in niacin are observed to lose weight and exhibit anorexia, weakness, and apathy (NRC, 2006). Thick saliva with a foul odor is drooled from the mouth. The oral cavity is characterized by ulceration of the upper palate, and the tongue is fiery red in color with ulceration and congestion along the anterior border. The fur may be unkempt and diarrhea is present. The ability of the cat to store the vitamin is limited since cats on a deficient diet were unable to maintain weight gain after 20 days. Adult cats lost weight and eventually died. An association with respiratory disease was common and contributed to early deaths (Carvalho de Silva et al., 1952).

 

Fortification Considerations

Pet foods that contain high quantities of meat and meat by-products should be adequate in available niacin. In the past, clinical “sore mouth” or “black tongue” was rarely seen in dogs unless they consumed diets very high in corn or corn products, such as grits or corn bread. Much of niacin contained in common feeds (plant sources) is in a bound form that is not available to animals. In formulating pet diets, therefore, niacin values for corn and other cereal grains and their by-product feeds should be disregarded. It is best to assume that these feeds provide no available niacin for dogs or cats. The dog and most species (except the cat, mink and some fish) 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. If pet food diets were based on corn, they would not contain large excesses of tryptophan. Tryptophan concentrations are not only low in corn but are largely unavailable. Therefore, one should ensure that dog diets are adequate in niacin, since it is inexpensive and it would be poor economics to satisfy niacin needs by the more expensive tryptophan.

Some work suggests that the D-isomer of tryptophan is poorly utilized by the dog for niacin synthesis, with efficiency of utilization of D-tryptophan for growth by the dog to be about one-third that of L-tryptophan (Czaranecki and Baker, 1982). Although excess tryptophan may meet the niacin requirement of dogs, it was demonstrated that oral or parenteral administration of tryptophan to niacin-deficient cats did not correct the deficiency (Carvalho de Silva et al., 1952). It was also observed that unlike most other species, cats were able to utilize niacin from raw corn (Braham et al., 1962).

Today, niacin deficiency occurs rarely since most commercial pet food products are fortified with niacin. Also, commercial processing of foods, such as boiling, blanching or canning, results in very small losses of niacin. Commercially produced niacin is quite stable compared to most other vitamins. Synthetic niacin and niacinamide were found to be stable in premixes with or without minerals for three months (Verbeeck, 1975). Gadient (1986) reports that niacin is stable 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. A recent report shows 98% retention of niacin in a vitamin premix after six months of storage; however, the retention was only 58% when the premix contained choline and trace minerals (Gadient, 1986).

 

Vitamin Safety

Harmful effects of nicotinic acid occur at levels far in excess of requirements (NRC, 1987). Nicotinic acid and niacinamide tolerance in cats has not been determined. Chen et al. (1938) reported the toxicity of nicotinic acid for dogs. They found that repeated oral administration of 2 g per day of nicotinic acid (133 to 145 mg per kg or 60.5 to 65.9 mg per lb of body weight) produced bloody feces in a few dogs. Convulsions and death followed. Doses of nicotinic acid as great as 0.5 g per day, which is about 36 mg per kg (16.4 mg per lb) body weight, produced slight proteinuria after eight weeks. Nicotinamide is two to three times more toxic than the free acid (Waterman, 1978).