Niacin (Vitamin B-3 Nicotinic Acid)

Niacin is a water-soluble vitamin, also known as vitamin B-3.

NIACIN

Niacin is a water-soluble vitamin, also known as vitamin B-3.  The term niacin refers to nicotinic acid and nicotinamide, which are both used by the body to form the coenzymes, nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phospate (NADP). Neither form is related to the nicotine found in tobacco, although their names are similar (1)

FUNCTION

Oxidation-reduction (redox) reactions:  Living organisms derive most of their energy from oxidation-reduction (redox) reactions, which are processes involving the transfer of electrons. As many as 200 enzymes require the niacin coenzymes, NAD and NADP, mainly to accept or donate electrons for redox reactions.  NAD functions most often in reactions involving the degradation (catabolism) of carbohydrates, fats, proteins, and alcohol to produce energy.  NADP functions more often in biosynthetic (anabolic) reactions, such as in the synthesis of fatty acids and cholesterol (1,2).

Non-redox reactions: The niacin coenzyme, NAD, is the substrate(reactant) for two classes of enzymes (mono-ADP-ribosyltransferases and poly-ADP-ribose polymerase) that separate the niacin moiety from NAD and transfer ADP-ribose to proteins.  Mono-ADP-ribosyltransferase enzymes were first discovered in certain bacteria where they were found to produce toxins such as those of cholera and diptheria. These enzymes and their products, ADP-ribosylated proteins, have also been found in the cells of mammals and are thought to play a role in cell signaling by affecting G-protein activity (3).  G-proteins are proteins that bind guanosine-5\’-triphosphate (GTP) and act as intermediaries in a number of cell-signaling pathways. Poly-ADP-ribose polymerases (PARPs) are enzymes that catalyze the transfer of many ADP-ribose units from NAD to acceptor proteins. PARPs appear to function in DNA replication and repair, as well as cell differentiation, suggesting a possible role for NAD in cancer prevention (2). At least 5 different PARPs have been identified, and although their functions are not yet well understood, their existence indicates a potential for considerable consumption of NAD (4). A third class of enzyme (ADP-ribosyl cyclase) catalyzes the formation of cyclic ADP-ribose, a molecule that works within cells to provoke the release of calcium ions from internal storage sites, and probably also plays a role in cell signaling (1).

DEFICIENCY

Pellagra: The late stage of severe niacin deficiency is known as pellagra. Early records of pellagra followed the widespread cultivation of corn in Europe in the 1700\’s (1). The disease was generally associated with the poorer social classes whose chief dietary staple consisted of cereals, like corn or sorghum. Pellagra was also common in the southern United States during the early 1900\’s where income was low and corn products were a major dietary staple (5). Interestingly, pellagra was not known in Mexico, where corn was also an important dietary staple and much of the population was also poor.  In fact, corn contains appreciable amounts of niacin, but it is present in a bound form that is not nutritionally available to humans.  The traditional preparation of corn tortillas in Mexico involves soaking the corn in a lime (calcium oxide) solution, prior to cooking. This process (heating in an alkaline medium) results in the release of bound niacin, increasing its bioavailability (6).

 The most common symptoms of niacin deficiency involve the skin, digestive system, and the nervous system. The symptoms of pellagra were commonly referred to as the four D\’s: dermatitis, diarrhea, dementia, and death.  In the skin, a thick, scaly, darkly pigmented rash develops symmetrically in areas exposed to sunlight.  The word “pellagra” comes from the Italian phrase for rough or raw skin. Symptoms related to the digestive system include a bright red tongue, vomiting, and diarrhea. Neurologic symptoms include headache, apathy, fatigue, depression, disorientation, and memory loss. If untreated, pellagra is ultimately fatal.

Nutrient interrelationships (tryptophan and niacin): In addition to its synthesis from dietary niacin, NAD may also be synthesized in the liver from the dietary amino acid, tryptophan. The synthesis of niacin from tryptophan also depends on enzymes that require vitamin B-6 and riboflavin, as well as an enzyme containing heme (iron). On average, 1 mg of niacin can be synthesized from the ingestion of 60 mg of tryptophan. Thus, 60 mg of tryptophan are considered to be 1 mg of niacin equivalents (NE). However, studies of pellagra in the southern United States during the early twentieth century indicated that the diets of many individuals who suffered from pellagra contained enough NE to prevent pellagra (3), challenging the idea that 60 mg of dietary tryptophan are equivalent to 1 mg of niacin. One study, in particular, found that the tryptophan content of the diet had no effect on the decrease in red blood cell niacin content that resulted from decreased dietary niacin in young men (7)

Causes of niacin deficiency: Niacin deficiency or pellagra may result from inadequate dietary intake of niacin and/or tryptophan. As mentioned above, other nutrient deficiencies may also contribute to the development of niacin deficiency. Patients with Hartnup\’s disease, a hereditary disorder resulting in defective tryptophan absorption, have developed pellagra. Carcinoid syndrome, a condition of increased secretion of serotonin and other catecholamines by carcinoid tumors, may also result in pellagra due to increased utilization of dietary tryptophan for serotonin rather than niacin synthesis. Prolonged treatment with the anti-tuberculosis drug Isoniazid has also resulted in niacin deficiency (see Drug Interactions).

The Recommended Dietary Allowance (RDA): The RDA for niacin, revised in 1998, was based on the prevention of deficiency.  Pellagra can be prevented by about 11 mg NE/day, but 12 mg to16 mg/day has been found to normalize the urinary excretion of niacin metabolites (breakdown products) in healthy young adults. Because pellagra represents severe deficiency, the Food and Nutrition Board chose to use the excretion of niacin metabolites as an indicator of niacinstatus rather than symptoms of pellagra (8). However, some researchers feel that cellular NAD and NADP content may be more relevant indicators of niacin nutritional status (9)

Adult men of all ages: 16 milligrams (mg) of niacin equivalents (NE*)/day
Adult women of all ages: 14 mg of NE/day
*1 mg NE = 60 mg of tryptophan = 1 mg niacin

DISEASE PREVENTION

Cancer: Studies of cultured cells in vitro provide evidence that NAD content influences the cellular response to DNA damage, an important risk factor for cancer.  Cellular NAD is consumed in the synthesis of ADP-ribose polymers, which play a role in DNA repair, and cyclic ADP-ribose may mediate cell-signaling pathways important in the prevention of cancer (see Function). Additionally, cellular NAD content has been found to influence levels of the tumor suppressor protein, p53, in human breast, skin, and lung cells (10). Neither the cellular NAD content nor the dietary intake of NAD precursors (niacin and tryptophan) necessary for optimizing protective responses following DNA damage has been determined, but they are likely to be higher than required for the prevention of pellagra. Little is known regarding cellular NAD levels and the prevention of DNA damage in humans.  Elevation of NAD levels in blood lymphocytes after supplementation of two healthy individuals with 100 mg/day of nicotinic acid for eight weeks reduced DNA strand breaks in lymphocytes exposed to free radicals in a test tube assay compared to those of non-supplemented individuals (11). More recently, nicotinic acid supplementation of up to 100 mg/day in 21 healthy smokers failed to provide any evidence of a decrease in cigarette smoke-induced genetic damage in blood lymphocytes compared to placebo (12).

Generally, relationships between dietary factors and cancer are established first in epidemiologic studies and followed up by basic cancer research on the cellular level.  In the case of niacin, research on biochemical and cellular aspects of DNA repair have stimulated an interest in the relationship between niacin intake and cancer risk in human populations (13). Recently, a large case control study found increased consumption of niacin, along with antioxidant nutrients, to be associated with decreased incidence of oral, pharyngeal, and esophageal cancers in northern Italy and Switzerland (14,15).  An increase in niacin intake of 6.2 mg was associated with about a 40% decrease in cases of cancers of the mouth (oral) and throat (pharyngeal), while a 5.2 mg increase in niacin intake was associated with a similar decrease in cases of cancer of theesophagus.

Insulin-dependent diabetes mellitus (IDDM): Insulin-dependent diabetes mellitus in children is known to result from the autoimmune destruction ofinsulin-secreting beta (b)-cells in the pancreas.  Prior to the onset of symptomatic diabetes (i.e., elevated blood glucose) specific antibodies, including islet cell antibodies (ICA), can be detected in the blood of high-risk individuals. The ability to detect individuals at high risk for the development of IDDM has led to the enrollment of high-risk siblings of children diagnosed with IDDM into trials designed to prevent its onset. Evidence from in vitro and animal research indicates that high levels of nicotinamide protect b-cells from damage by toxic chemicals, inflammatory white blood cells, and reactive oxygen species.Pharmacologic doses of nicotinamide (up to 3 grams/day) were first used to protect b-cells in patients shortly after the onset of IDDM.  An analysis of ten published trials (five placebo-controlled) found evidence of improved b-cell function after one year of treatment with nicotinamide, but failed to find any clinical evidence of improved glycemic (blood glucose) control (16). Recently, high doses of nicotinamide were found to decrease insulin sensitivity in high-risk relatives of IDDM patients (17), which might explain the finding of improved b-cell function without concomitant improvement in glycemic control. Several pilot studies for the prevention of IDDM in ICA-positive relatives of patients with IDDM yielded conflicting results, while a large randomized trial in school children that was not placebo-controlled found a significantly lower incidence of IDDM in the nicotinamide-treated group. A large multi-centerrandomized placebo-controlled trial of nicotinamide in ICA-positive siblings of IDDM patients (aged 3 – 12 years) recently failed to find a difference in the incidence of IDDM after 3 years (16).  Another large multicenter trial of nicotinamide in high-risk relatives of IDDM patients is presently in progress.  Unlike nicotinamide, nicotinic acid has not been found effective in the prevention of IDDM.

DISEASE TREATMENT

High cholesterol and cardiovascular diseases: Pharmacologic doses of nicotinic acid, but not nicotinamide, have been known to reduce blood cholesterol since 1955 (18).  Only one randomized placebo-controlled multicenter trial examined the effect of nicotinic acid therapy alone (3 grams daily) on outcomes of cardiovascular disease.  The Coronary Drug Project (CDP) followed over 8,000 men with a previous myocardial infarction (heart attack) for 6 years. In the group that took 3 grams of nicotinic acid daily total blood cholesterol decreased by an average of 10%, triglycerides decreased by 26%, recurrent nonfatal myocardial infarction decreased by 27%, andcerebrovascular events (stroke + transient ischemic attacks) decreased by 26% compared to the placebo group. Though nicotinic acid therapy did not decrease total deaths or deaths from cardiovascular disease during the 6-year study period, post-trial follow up 9 years later revealed a 10% reduction in total deaths (19). Four out of five major cardiovascular outcome trials found nicotinic acid in combination with other therapies to be of statistically significant benefit in men and women (20). Nicotinic acid therapy has been found to result in markedly increased HDL-cholesterol levels, as well as decreased serum Lp(a) lipoprotein concentrations, and a shift from small dense LDL particles to large, buoyant LDL particles, all of which are considered cardioprotective changes in blood lipid profiles.   Because of the adverse side effects associated with high doses of nicotinic acid (see Safety), it has most recently been used in combination with other lipid-lowering medications in slightly lower doses (18). A recent randomized clinical trial found that a combination of nicotinic acid (2 to 3 grams/day) and a cholesterol-lowering drug (simvastatin) resulted in greater benefits on blood lipid profiles and cardiovascular events, such as heart attack and stroke, than simvastatin alone in patients with coronary artery disease and low HDL levels (21). Although it is a nutrient, at the pharmacologic dose required for cholesterol-lowering effects, the use of nicotinic acid should be approached as if it were a drug.  Individuals should only undertake cholesterol-lowering therapy with nicotinic acid under the supervision of a qualified health care provider, so that the potential for adverse effects may be minimized and treatment benefit maximized.

HIV/AIDS: It has been hypothesized that infection with Human Immunodeficiency Virus (HIV), the virus that causes Acquired Immunodeficiency Syndrome (AIDS), increases the risk of niacin deficiency. Interferon-gamma (IF-g) is a cytokine produced by cells of the immune system in response to infection. IF-g levels are elevated in individuals infected with HIV, and higher IF-g levels have been associated with poorer prognosis.  By stimulating the enzyme, indoleamine 2,3 dioxygenase (IDO), IF-g is known to increase the breakdown of tryptophan, a niacin precursor, supporting the idea that infection with HIV increases the risk of niacin deficiency (22). A study of 281 HIV-positive men found that higher levels of niacin intake were associated with decreased progression rate to AIDS and improved survival (23).

FOOD SOURCES

Good sources of niacin include yeast, meat, poultry, fish with red meat (e.g., tuna, salmon), cereals (especially fortified cereals), legumes, and seeds.  Milk, green leafy vegetables, coffee, and tea also provide some niacin (3). In plants, especially mature cereal grains like corn and wheat, niacin may be bound to large molecules in the form of glycosides, significantly decreasing niacinbioavailability (6).

In the United States, the average intake of niacin is about 30 mg/day for young adult men, and 20 mg/day for young adult women.  In a sample of adults over the age of 60, men were found to have an average dietary intake of 21 mg/day and women 17 mg/day (8). Some foods with substantial amounts of niacin are listed in the table below along with their niacin content in milligrams (mg). Food composition tables (like the one below) generally list niacin content without including niacin equivalents (NE) from tryptophan, or any adjustment for niacin bioavailability.  For more information on the nutrient content of foods you eat frequently, search the USDA food composition database.

Food Serving Niacin (mg)
Chicken (light meat) 3 ounces* (cooked without skin) 10.6
Turkey (light meat) 3 ounces (cooked without skin) 5.8
Beef (lean) 3 ounces (cooked) 3.1
Salmon 3 ounces (cooked) 8.5
Tuna (light, packed in water) 3 ounces 11.3
Bread (whole wheat) 1 slice 1.1
Cereal (unfortified) 1 cup 5-7
Cereal (fortified) 1 cup 20-27
Pasta (enriched) 1 cup (cooked) 2.3
Peanuts 1 ounce (dry roasted) 3.8
Lentils 1 cup (cooked) 2.1
Lima beans 1 cup (cooked) 1.8
Coffee (brewed) 1 cup 0.5

*A 3-ounce serving of meat is about the size of a deck of cards.

SAFETY

Toxicity: Niacin from foods is not known to cause adverse effects.  Although one study noted adverse effects from the consumption of bagels to which were added 60 times the normal amount of niacin fortification, most adverse effects have been reported with pharmacologic preparations of niacin (8).

Nicotinic acid: Flushing, itching and gastrointestinal disturbances such as nausea and vomiting are common. Hepatotoxicity (liver cell damage), including elevated liver enzymes and jaundice, has been observed at intakes as low as 750 mg of nicotinic acid/day for less than 3 months.Hepatitis has been observed with sustained-released nicotinic acid on as little as 500 mg/day for 2 months (24).  However, almost all reports of severe hepatitis have been associated with the slow-release form of nicotinic acid at doses of 3 to 9 grams per day used to treat high cholesterol for months or years (8). Immediate-release (crystalline) nicotinic acid appears to be less toxic to the liver. Skin rashes and dry skin have been noted with nicotinic acid supplementation. Transient episodes of low blood pressure (hypotension) and headache have also been reported. Large doses of nicotinic acid have been observed to impair glucose tolerance, likely due to decreased insulin sensitivity.  Impaired glucose-tolerance in susceptible (pre-diabetic) individuals could result in elevated blood glucose levels and clinical diabetes. Elevated blood levels of uric acid, occasionally resulting in attacks ofgout in susceptible individuals, have also been observed with high-dose nicotinic acid therapy (24). Nicotinic acid at doses of 1.5 to 5 grams per day has resulted in a few case reports of blurred vision, and other eye problems, which have generally been reversible upon discontinuation. People with abnormal liver function or a history of liver disease, diabetes, active peptic ulcer disease, gout, cardiac arrhythmias, inflammatory bowel disease, migraine headaches, and alcoholism may be more susceptible to the adverse effects of excess nicotinic acid intake than the general population (8).

Nicotinamide: Nicotinamide is generally better tolerated than nicotinic acid (25).  It does not generally cause flushing.  However, nausea, vomiting, and signs of liver toxicity (elevated liver enzymes, jaundice) have been observed at doses of 3 grams/day (23).   Nicotinamide has resulted in decreased insulin sensitivity at doses of 2 grams/day in adults at high risk of insulin-dependent diabetes (17).

Flushing of the skin primarily on the face, arms, and chest is a common side effect of nicotinic acid and may occur initially at doses as low as 30 mg/day.  Although flushing on nicotinamide is rare, the Food and Nutrition Board set the tolerable upper intake level (UL) for niacin (nicotinic acid and nicotinamide) at 35 mg/day to avoid the adverse effect of flushing in the general population. The UL is not meant to apply to individuals who are being treated with a nutrient under medical supervision, as should be the case with high-dose nicotinic acid for elevated blood cholesterol levels (8).

Drug interactions: Coadministration of nicotinic acid with lovastatin (another cholesterol lowering medication) may have resulted in rhabdomyolysis in a small number of case reports. Rhabdomyolysis is a relatively uncommon condition in which muscle cells are broken down, releasing muscle enzymes and electrolytes into the blood, sometimes resulting in kidney failure. Sulfinpyrazone is a medication for the treatment of gout that promotes excretion of uric acid from the blood into urine. Nicotinic acid may inhibit this “uricosuric” effect of sulfinpyrazone (24).  Long-term administration of the cancer chemotherapy agent, 5-Fluorouracil (5-FU), has been reported to cause symptoms of pellagra. Niacin supplementation is recommended during long-term treatment of tuberculosis with isoniazid. Isoniazid is a niacin antagonist and long-term treatment has resulted in pellagra-like symptoms (25). Estrogen and estrogen-containing oral contraceptives increase the efficiency of niacin synthesis from tryptophan, resulting in a decreased dietary requirement for niacin (2).

THE LINUS PAULING INSTITUTE RECOMMENDATION

The optimum intake of niacin for health promotion and chronic disease prevention is not yet known.  The RDA (16 mg NE/day for men and 14 mg NE/day for women) is easily obtainable in a varied diet and should prevent deficiency in most people.  Following the Linus Pauling Institute recommendation to take a daily multivitamin/mineral supplement, containing 100 % of the Daily Value (DV) for niacin, will provide at least 20 mg of niacin daily.

Older adults: (65 years and older): Dietary surveys indicate that 15% to 25% of older adults do not consume enough niacin in their diets to meet the RDA (16 mg NE/day for men and 14 mg NE/day for women), and that dietary intake of niacin decreases between the ages of 60 and 90 years. Thus, it is advisable for older adults to supplement their dietary intake with a multivitamin/multimineral supplement, which will generally provide at least 20 mg of niacin daily. 

REFERENCES

1.  Brody, T. Nutritional Biochemistry, 2nd Edition. San Diego, CA: Academic Press, 1999:  pages 593-602.

2.  Cervantes-Laurean, D. et al. Niacin. In Shils, M. et al. Eds. Nutrition in Health and Disease, 9th Edition. Baltimore: Williams & Wilkins, 1999: pages 401-411.

3.  Jacob, R. & Swenseid, M. Niacin. In Ziegler, E.E. & Filer, L.J. Eds. Present Knowledge in Nutrition. Washington D.C.: ILSI Press, 1996: pages 185-190.

4.  Jacobson, M.K. & Jacobson, E.L. Discovering new ADP-ribose polymer cycles: protecting the genome and more. Trends in Biochemical Science. 1999; volume 24: pages 415-417.

5.  Park, Y. et al. Effectiveness of food fortification in the United States: the case of pellagra. American Journal of Public Health. 2000; volume 90: pages 727-38.(PubMed)

6.  Gregory, J. Nutritional properties and significance of vitamin glycosides. Annual Review of Nutrition. 1998; volume 18: pages 227-296.  (PubMed)

7.   Jacobson, E.L. & Jacobson, M.K. Tissue NAD as a biochemical measure of niacin status in humans. Methods in Enzymology. 1997; volume 280: pages 221-230.

8.  Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B-6, Vitamin B-12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academy Press, 1998: pages 123-149. (National Academy Press)

9.  Fu, C.S. et al. Biochemical markers for assessment of niacin status in young men: levels of erythrocyte niacin coenzymes and plasma tryptophan. Journal of Nutrition. 1989; volume 119: pages 1949-55.  (PubMed)

10.  Jacobson, E.L. et al. Mapping the role of NAD metabolism in prevention and treatment of carcinogenesis. Molecular and Cellular Biochemistry. 1999; volume 193: pages 69-74. (PubMed)

11.  Weitberg, AB. Effect of nicotinic acid supplementation on oxygen radical-induced genetic damage in human lymphocytes. Mutation Research. 1989; volume 216: pages 197-201. (PubMed)

12.  Hageman, G. et al. Nicotinic acid supplementation: effects on niacin status, cytogenetic damage, and poly(ADP-ribosylation) in lymphocytes of smokers. Nutrition and Cancer. 1998; volume 32: pages 113-20.  (PubMed)

13.  Jacobson E. Niacin deficiency and cancer in women. Journal of the American College of Nutrition. 1993; volume 12: pages 412-416.  (PubMed)

14.  Negri, E. Selected micronutrients and oral and pharyngeal cancer. International Journal of Cancer. 2000; volume 86: pages 122-127. (PubMed)

15.  Franceschi, S. Role of macronutrients, vitamins, and minerals in the aetiology of squamous-cell carcinoma of the oesophagus. International Journal of Cancer. 2000; volume 86: pages 626-631.  (PubMed)

16.  Lampeter, E. et al. The Deutsche Nicotinamide Intervention Study: an attempt to prevent type 1 diabetes. Diabetes. 1998; volume 47: pages 980-984. (PubMed)

17.  Greenbaum, C.J. et al. Nicotinamide\’s effects on glucose metabolism in subjects at risk for IDDM. Diabetes. 1996; volume 45: pages 1631-1634. (PubMed)

18.  Knopp, R. Drug treatment of lipid disorders. The New England Journal of Medicine. 1999; volume 341: pages 498-511.

19.  Canner, P.L. et al. Fifteen year mortality in Coronary Drug Project patients: long term benefit of niacin. Journal of the American College of Cardiology. 1986; volume 81: pages 1245-55. (PubMed)

20.  Guyton, J. Effect of niacin on atherosclerotic cardiovascular disease. American Journal of Cardiology. 1998; volume 82; pages 18U-23U. (PubMed)

21. Brown, B.G. et al. Simvastatin and niacin, antioxidant vitamins or the combination for the prevention of coronary disease. The New England Journal of Medicine. 2001; volume 345: pages 1583-1592. (PubMed)

22.  Brown, R. et al. Implications of interferon-induced tryptophan catabolism in cancer, autoimmune diseases and AIDS. Advances in Experimental Medicine and Biology. 1991; volume 294: pages 425-35. (PubMed)

23.  Tang, A. et al. Effects of micronutrient intake on survival in human immunodeficiency virus type 1 infection. American Journal of Epidemiology. 1996; volume 143:  pages 1244-56.  (PubMed)

24.  Vitamins. In Drug Facts and Comparisons. St. Louis, MO: Facts and Comparisons, 1999: pages 6-33.

25.  Flodin, N. Pharmacology of Micronutrients. New York, NY: Alan R. Liss, Inc., 1988: pages 136-139

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