Niacin

Niacin is a water-soluble vitamin, which is also known as nicotinic acid or vitamin B3. Nicotinamide is the derivative of niacin and used by the body to form the coenzymes nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). The chemical structure of the various forms of niacin are shown in the diagram. None of the forms are related to the nicotine found in tobacco, although their names are similar.

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 energy producing reactions involving the degradation (catabolism) of carbohydrates, fats, proteins, and alcohol. NADP functions more often in biosynthetic (anabolic) reactions, such as in the synthesis of fatty acids and cholesterol.

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 (diagram). Mono-ADP-ribosyltransferase enzymes were first discovered in certain bacteria, where they were found to produce toxins, such as 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. 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 in cell differentiation, suggesting a possible role for NAD in cancer prevention. At least five different PARPs have been identified, and although their functions are not yet well understood, their existence indicates a potential for considerable consumption of NAD. A third class of enzymes (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.

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. The disease was generally associated with 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. 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. Heating the corn in an alkaline solution results in the release of bound niacin, increasing its bioavailability.

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. In fact, 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 interactions (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 B6 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 U.S. during the early twentieth century indicated that the diets of many individuals who suffered from pellagra contained enough NE to prevent pellagra, challenging the idea that 60 mg of dietary tryptophan are equivalent to 1 mg of niacin. In particular, one study in young men found that the tryptophan content of the diet had no effect on the decrease in red blood cell niacin content that resulted from low dietary niacin.

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. For instance, 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. Further, prolonged treatment with the anti-tuberculosis drug, Isoniazid, has resulted in niacin deficiency.

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 in cancer development. Cellular NAD is consumed in the synthesis of ADP-ribose polymers, which play a role in DNA repair, and cyclic ADP-ribose may also mediate cell-signaling pathways important in cancer prevention. Additionally, cellular depletion of NAD has been found to decrease levels of the tumor suppressor protein, p53, in human breast, skin, and lung cells. 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 both are likely to be higher than that required for the prevention of pellagra. Niacin deficiency was found to decrease bone marrow NAD and poly-ADP-ribose levels and increase the risk of chemically induced leukemia. Moreover, one study reported that niacin supplementation decreased the risk of ultraviolet light-induced skin cancers in mice. However, little is known regarding cellular NAD levels and the prevention of DNA damage or cancer in humans. One study in two healthy individuals involved elevating NAD levels in blood lymphocytes by supplementation with 100 mg/day nicotinic acid/day for eight weeks. Compared to non-supplemented individuals, the supplemented individuals had reduced DNA strand breaks in lymphocytes exposed to free radicals in a test tube assay. 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.

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

Insulin-dependent diabetes mellitus (IDDM)

Insulin-dependent diabetes mellitus in children, often called type I diabetes, is known to result from the autoimmune destruction of insulin-secreting beta-cells in the pancreas. Prior to the onset of symptomatic diabetes, 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 led to the enrollment of high-risk siblings of children with IDDM into trials designed to prevent its onset. Evidence from in vitro and animal research indicates that high levels of nicotinamide protect beta-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 beta-cells in patients shortly after the onset of IDDM. An analysis of ten published trials (five placebo-controlled) found evidence of improved beta-cell function after one year of treatment with nicotinamide, but the analysis failed to find any clinical evidence of improved glycemic (blood glucose) control. Recently, high doses of nicotinamide were found to decrease insulin sensitivity in high-risk relatives of IDDM patients, which might explain the finding of improved beta-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, whereas 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-center randomized controlled trial of nicotinamide in ICA-positive siblings of IDDM patients between three and 12 years of age recently failed to find a difference in the incidence of IDDM after three years. 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 disease

Pharmacologic doses of nicotinic acid, but not nicotinamide, have been known to reduce serum cholesterol since 1955. Today, niacin is commonly prescribed with other lipid-lowering medications. However, one randomized, placebo-controlled, multicenter trial examined the effect of nicotinic acid therapy (three grams daily), alone, on outcomes of cardiovascular disease. Specifically, the Coronary Drug Project (CDP) followed over 8,000 men with a previous myocardial infarction (heart attack) for six years. Compared to the placebo group, the group that took three grams of nicotinic acid daily experienced an average 10% reduction in total blood cholesterol, a 26% decrease in triglycerides, a 27% reduction in recurrent nonfatal myocardial infarction, and a 26% reduction in cerebrovascular events (stroke + transient ischemic attacks). Although nicotinic acid therapy did not decrease total deaths or deaths from cardiovascular disease during the six-year study period, post-trial follow up nine years later revealed a 10% reduction in total deaths with nicotinic acid treatment. 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. Nicotinic acid therapy markedly increases HDL-cholesterol levels, decreases serum Lp(a) (lipoprotein-a) concentrations, and shifts small, dense LDL particles to large, buoyant LDL particles; all of these changes in the blood lipid profile are considered cardioprotective.

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. A recent randomized controlled trial found that a combination of nicotinic acid (2 to 3 grams/day) and a cholesterol-lowering drug (simvastatin) resulted in greater benefits on serum HDL levels and cardiovascular events, such as heart attack and stroke, than placebo in patients with coronary artery disease and low HDL levels. However, an antioxidant combination (vitamin E, vitamin C, selenium, and beta-carotene) appeared to blunt the beneficial effects of niacin plus simvastatin. The effects of niacin are dose-dependent. A placebo-controlled study in 39 patients taking statins (cerivastatin, atorvastatin, or simvastatin) found that a very low dose of niacin, 100 mg daily, increased HDL cholesterol by only 2.1 mg/dL, and the combination had no effect on LDL cholesterol, total cholesterol, or triglyceride levels. Doses of niacin higher than 1 gram/day are typically used to treat hyperlipidemia. A few case reports have raised concerns that concurrent use of niacin and statins may result in myopathy; however, clinical trials have not confirmed such adverse effects.

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 in order to minimize potentially adverse effects and maximize therapeutic benefits.

HIV/AIDS

It has been hypothesized that infection with human immunodeficiency virus (HIV), the virus that causes acquired immmunodeficiency 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 prognoses. By stimulating the enzyme, indoleamine 2,3 dioxygenase (IDO), IF-g increases the breakdown of tryptophan, a niacin precursor, thus supporting the idea that HIV infection increases the risk of niacin deficiency. In a very small, uncontrolled study, treatment of four HIV positive individuals with 1,000 to 1,500 mg/day of nicotinamide for two months resulted in 40% increases in plasma tryptophan levels. An observational study of 281 HIV-positive men found that higher levels of niacin intake were associated with decreased progression rate to AIDS and improved survival.

Safety

Toxicity

Niacin from foods is not known to cause adverse effects. Although one study noted adverse effects following consumption of bagels with 60 times the normal amount of niacin fortification, most adverse effects have been reported with pharmacologic preparations of niacin.

Nicotinic acid

Common side effects of nicotinic acid include flushing, itching, and gastrointestinal disturbances such as nausea and vomiting. 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 three months. Hepatitis has been observed with timed-release nicotinic acid at dosages as little as 500 mg/day for two months, although almost all reports of severe hepatitis have been associated with the timed-release form of nicotinic acid at doses of 3 to 9 grams per day used to treat high cholesterol for months or years. Immediate-release (crystalline) nicotinic acid appears to be less toxic to the liver than extended release forms. Immediate-release nicotinic acid is often used at higher doses than timed-release forms, and severe liver toxicity has occurred in individuals who substituted timed-release niacin for immediate-release niacin at equivalent doses. 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 of gout in susceptible individuals, have also been observed with high-dose nicotinic acid therapy. Nicotinic acid at doses of 1.5 to 5 grams/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.

Nicotinamide

Nicotinamide is generally better tolerated than nicotinic acid. 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. Nicotinamide has resulted in decreased insulin sensitivity at doses of 2 grams/day in adults at high risk for insulin-dependent diabetes.

The tolerable upper intake level (UL)

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 from 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. The UL applies to the general population and 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.

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. A 3-year randomized controlled trial in 160 patients with documented coronary heart disease (CHD) and low HDL levels found that a combination of simvastatin (Zocor) and niacin increased HDL2 levels, inhibited the progression of coronary artery stenosis (narrowing), and decreased the frequency of cardiovascular events such as myocardial infarction and stroke. However, concurrent therapy with antioxidants (1000 mg/d vitamin C, 800 IU/d alpha-tocopherol, 100 mcg/d of selenium, and 25 mg/d beta-carotene) diminished the protective effects of the simvastatin-niacin combination. Although the mechanism for these effects is not known, some scientists have questioned the benefit of concurrent antioxidant therapy in patients on lipid lowering agents.

Several other medications may interact with niacin therapy or with absorption and metabolism of the vitamin. 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. Long-term administration of the cancer chemotherapy agent, 5-Fluorouracil (5-FU), has been reported to cause symptoms of pellagra, and thus niacin supplementation may be needed. Niacin supplementation is also recommended during long-term treatment of tuberculosis with isoniazid, a niacin antagonist, because such treatment has resulted in pellagra-like symptoms. Further, estrogen and estrogen-containing oral contraceptives increase the efficiency of niacin synthesis from tryptophan, resulting in a decreased dietary requirement for niacin.

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.

Reference: http://lpi.oregonstate.edu/infocenter/vitamins/niacin/