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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

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48 Vitamin Tolerance of Animals o 11 '': OCR for page 47
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.

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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. REFERENCES Andersson, R. G. G., G. Aberg, R. Brattsand, E. Ericsson, and L. Lundholm. 1977. Studies on the mechanism of flush induced by nicotinic acid. Acta Pharmacol. Toxicol. 41:1. Baker, D. H., J. T. Yen, A. H. Jensen, R. G. Teeter, E. N. Michel, and J. H. Burns. 1976. Niacin activity in niacinamide and coffee. Nutr. Rep. Int. 14:115. Blum, C. B., R. I. Levy, S. Eisenberg, M. Hall, R. H. Goebel, and M. Berman.1977. High density lipoprotein metabolism in man. J. Clin. Invest. 60:795. Bourgeois, B. F. D., W. E. Dobson, and J. A. Ferrendelli.1983. Poten- tiation of the antiepileptic activity of phenobarbital by nicotinamide. Epilepsia 24:238. Byrne, D. H., and P. A. Kitos.1983. Teratogenic effects of cholinergic insecticides in chick embryos. Biochem. Pharmacol. 32:2881. Chen, K. K., C. L. Rose, and E. B. Robbins.1938. Toxicity of nicotinic acid. Proc. Soc. Exp. Biol. Med. 38:241. Dalton, C., T. C. Van Trabert, and J. X. Dwyer. 1970. Relation of nicotinamide and nicotinic acid to hypolipidemia. Biochem. Phar- macol. 19:2609. Elvehjem, C. A., R. J. Madden, F. M. Strong, and D. W. Woopley. 1938. The isolation and identification of the anti-black tongue fac- tors. J. Biol. Chem. 123:137. Frank, T. J., and L. H. Schultz. 1979. Oral nicotinic acids as a treat- ment for ketosis. J. Dairy Sci. 62:1804. Funk, C. 1911. On the chemical nature of the substances which cure polyneuritis in birds induced by a polished rice diet. J. Physiol. 43:395. Gershon, S. L., and I. H. Fox.1974. Pharmacologic effects of nicotinic acid on human purine metabolism. J. Lab. Clin. Med. 84:179. Ghosh, H. P., P. K. Sarkar, and B. C. Guha. 1963. Distribution of the bound form of nicotinic acid in natural materials. J. Nutr. 79:451. Gulbert, K., and J. T. Huber. 1979. Influence of supplemental niacin with and without non-protein nitrogen in the performance of lactat- ing dairy cows. J. Dairy Sci. 62:78. Hankes, L. V. 1984. Nicotinic acid and nicotinamide. Pp. 329-377 in Handbook of Vitamins, Nutritional, Biochemical, and Clinical As- pects. L. J. Machlin, ed. New York: Marcel Dekker. Hawkins, D. R.1968. Treatment of schizophrenia based on the medi- cal model. J. Schiz.2:3. Hoffer, A. 1969. Safety, side effects and relative lack of toxicity of nicotinic acid and nicotinamide. Schizophrenia 1:78. Horrobin, D. F. 1980. Schizophrenia: A biochemical disorder? Bio- medicine 32:54. Jaster, E. H., G. F. Hartwell, and M. F. Hutjens.1983. Feeding supple- mental niacin for milk production in six dairy herds. J. Dairy Sci. 66:1046. Kamat, J. P., L. M. Narurkar, N. A. Mhatre, and M. V. Narurkar.1980. Nicotinamide induced hepatic microsomal mixed function oxidase system in rats. Biochem. Biophys. Acta 628:26. Kazumi, T., G. Yoshino, S. Fuji, and S. Baba. 1978. Tumorigenic action of streptozotocin on the pancreas and kidney in male Wistar rats. Cancer Res. 38:2144. Matschke, G. H., and K. A. Fagerstone. 1977. Teratogenic effects of 6-aminonicotinamide in mice. J. Toxicol. Environ. Health 3:735. Pamukuo, A. M., U. Milli, and G. T. Bryan.1981. Protective effect of nicotinamide on bracken fern induced carcinogenicity in rats. Nutr. Cancer 3:86. Patsch, J. R., D. Yeshurm, R. L. Jackson, and A. M. Gotto. 1977. Effects of clofibrate, nicotinic acid and diet on the properties of the plasma lipoproteins in a subject with type III hyperlipoproteinemia. Am. J. Med. 63:1001. Riddell, D. O., E. E. Bartley, and A. D. Dayton. 1981. Effect of nico- tinic acid on microbial protein synthesis in vitro and on dairy cattle and milk production. J. Dairy Sci. 65:782. Robie, T. R. 1967. Cyproheptadine: An excellent antidote for niacin- induced hyperthermia. J. Schiz. 1:133. Schoental, R. 1977. The role of nicotinamide and of certain other modifying factors in diethylnitrosamine carcinogenesis: Fusaria mycotoxins and "spontaneous" tumors in animals and man. Cancer 40:1833. Smith, S. R.1981. Severe hypertriglyceridemia responding to insulin and nicotinic acid therapy. Postgrad. Med. J. 57:511. Spies, T. D., C. Copper, and M. A. Blankenhorn. 1938. The use of nicotinic acid in the treatment of pellagra. J. Am. Med. Assoc. 110:622. Subissi, A., P. Schiantrelli, M. Biagi, and G. Sardelli.1980. Compara- tive evaluation of some pharmacological properties and side effects of D-glucitol hexa nicotinate sorbinicate and nicotinic acid corre- lated with plasma concentration of nicotinic acid. Atherosclerosis 36:135. Svedmyr, M., A. Heggelund, and G. Aberg. 1977. Influence of indo- methacin on flush induced by nicotinic acid in man. Acta Pharmacol. Toxicol.41:397. Tsarichenko, G. V., V. I. Bobrov, and M. V. Starkov.1977. Toxicity of isonicotinic acid. Khom-Farm Zh. 11:45. Toth, B. 1983. Lack of carcinogenicity of nicotinamide and isonic- otinamide following lifelong administration to mice. Oncology 40:72. Uyeki, E. M., J. Doull, C. C. Cheng, and M. Misawa. 1982. Terato- genic and antiteratogenic effects of nicotinamide derivatives in chick embryos. J. Toxicol. Environ. Health 9:963. Warburg, O., and W. Christian~ 1936. Pyridine, the hydrogen-transfer- ring component of the fermentation enzymes (pyridine nucleotide). Biochem. Z. 287:291. Warburg, O., W. Christian, and A. Griese. 1935. Hydrogen-transfer- ring coenzyme, its composition and mode of action. Biochem. Z. 282:157. Wick, M. M., A. Rossini, and D. Glynn.1977. Reduction of streptozo- tocin toxicity by 3-0-methyl-D-glucose with enhancement of antitu- mor activity in murine ~-1210 leukemia. Cancer Res. 37:3901. Wilander, E., and R. Gunnarsson. 1975. Diabetogenic effects of n- nitromethylurea in the Chinese hamster. Acta Pathol. Microbiol. Scand. 83:206. Winter, S. L., and J. L. Boyer.1973. Hepatic toxicity from large doses of vitamin B-3 nicotinamide. N. Engl. J. Med.289:1180. Yoshino, G., T. Kazumi, S. Morita, N. Kobayashi, K. Terashi, and S. Baba. 1979. Glucagon secretion during development of insulin-se- creting tumors induced by streptozotocin and nicotinamide. Endo- crinol. Jpn.26:655. Zackheim, H. S. 1978. Topical 6-amino-nicotinamide plus oral nic- otinamide therapy for psoriasis. Arch. Dermatol. 114:1632.