Niacin – Vitamin B3 Facts

Niacin (also known as vitamin B₃ or nicotinic acid) is a water soluble vitamin. Other forms of vitamin B₃ include the corresponding amide and nicotinamide (“niacinamide”). Niacin cannot be directly converted to nicotinamide, but both compounds are precursors of the coenzymes nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). NAD converts to NADP in the presence of the enzyme NAD+ kinase. NADP and NAD are coenzymes. NAD is important in catabolism of fat, carbohydrate, protein, and alcohol, as well as cell signaling and DNA repair, and NADP mostly in anabolism reactions such as fatty acid and cholesterol synthesis. High energy requirements (brain) or high turnover rate (gut, skin) organs are usually the most susceptible to their deficiency. Although the two are identical in their vitamin activity, nicotinamide does not have the same pharmacological effects (lipid modifying effects) as niacin (1). Nicotinamide does not reduce cholesterol or cause flushing. Niacin is involved in both DNA repair and the production of steroid hormones in the adrenal gland.

A substantial amount of niacin can be synthesized from the amino acid tryptophan. Therefore, the niacin ade­quacy of diets involves both the level of the pre-formed vitamin and that of its potential precursor tryptophan. All animal species (including humans) appear to be capable, to varying degrees, of the synthesis of the metabolically active forms of niacin, NAD(H) and NADP(H). Biosynthesis occurs from the tryptophan metabolite quinolinic acid. The conversion of tryptophan to NAD is a generally ineffi­cient process. Humans appear normally to convert 60 mg of tryptophan to 1 mg of niacin. Niacin-deficient humans are estimated to use nearly 3% of dietary tryptophan for niacin biosynthesis, and thus are able to satisfy two-thirds of their requirement for the vita­min from the metabolism of this indispensable amino acid. It would appear that protein turnover may pre-empt niacin synthesis under conditions of limiting tryptophan. In such circumstances the amount of tryptophan available for niacin synthesis would be expected to be low, render­ing the calculation of niacin equivalents inaccurate.

Pyridoxine deficiency impairs the overall conversion of tryptophan to niacin. It does not, however, block the excretion of the urinary metabolites and this phenomenon has been exploited for the assessment of pyridoxine status by monitoring the urinary excretion of one metabolite, xanthurenic acid, after a tryptophan load. The conversion of tryptophan to niacin is also reduced by high-fat diets or diets containing excess leucine (2,3). These effects appear to be due to ketosis, which has been noted as a common feature of diets of individuals with pellagra. NAD synthesis appears to be increased by such factors as caloric restriction and hypoxia suggesting that NAD levels may serve as indicators of physiological stress.

It has been suggested that zinc plays some role in the pyridoxine-dependent metabolic interconversion of tryptophan to niacin. Pellagra patients have been found to have low plasma zinc levels (4). Studies have shown that treatment of niacin-deficient animals with the metabolic intermediate picolinic acid increases circu­lating zinc levels.

The predominant forms of niacin in most animal-derived foods are the coenzymes NAD(H) and NADP(H). These are digested to release nicotinamide, in which form the vitamin is absorbed. The cleav­age of nicotinamide to free nicotinic acid appears to be accomplished by intestinal microorganisms, and is believed to be of quanti­tative importance in niacin absorption. Niacin is absorbed in the stomach and small intes­tine. Niacin is transported in the plasma as both nicotinic acid and nicotinamide in unbound forms. Because the nicotinic acid is converted to NAD(H) and subsequently to nicotinamide in the intestine and liver, circu­lating levels of nicotinamide tend to exceed those of nicotinic acid. Both nicotinic acid and nicotinamide are taken up by most peripheral tis­sues by passive diffusion. However, some tissues have transport systems that facilitate niacin uptake. The brain takes up the vitamin by energy-dependent transport systems. A receptor for nicotinic acid has been identified in adipose tissue (5). It is also expressed in spleen and immune cells. The receptor appears to play roles in responses (flushing, antihyperlipidemic) to high doses of nicotinic acid.

Excretion involves a variety of water-soluble metabolites in the urine. At high rates of niacin intake, the vitamin is excreted predominantly (65–85% of total) in unchanged form. At all rates of intake, however, nicotinamide tends to be excreted as its metabolites more extensively than is nicotinic acid. Further, the bio­logical turnover of each vitamer is determined primarily by its rate of excretion; thus, at high intakes, the half-life of nicotinamde is shorter than that of nicotinic acid.

Historically, niacin deficiency which causes pellagra was prevalent among people who relied on maize (corn) as their major food sta­ple. Unlike thi­amin deficiency (which also involves a cereal-based diet), niacin deficiency more frequently results from poor bio­availability rather than scarcity per se. Niacin deficiency in animals is characterized by a variety of species-specific signs that are usually accompanied by loss of appetite and poor growth. The general progression of signs is captured as the “Four Ds of niacin deficiency: Dermatitis, Diarrhoea, Delirium and Death.

The dermato­logic changes, which are usually most prominent (being called pellagra), are most pronounced in the parts of the skin that are exposed to sunlight (face, neck, backs of the hands, and forearms) In some patients, lesions resemble early sunburn; in chronic cases the sym­metric lesions feature cracking, desquamation, hyper-keratosis, and hyperpigmentation. Alterations of the mucosa of the mouth, tongue, oesophagus, stomach (resulting in achlorhydria), and intestine (resulting in diarrhoea) also occur. Pellagra almost always involves anaemia. Early neurological symptoms associated with pellagra include anxiety, depression, and fatigue; later symptoms include depression, apathy, headache, dizziness, irritability, and tremors.

In general, the toxicity of niacin is low. The toxic poten­tial of nicotinamide appears to be greater than that of nicotinic acid, prob­ably by a factor of four (6). The most common side effect of high-dose nicotinic acid is caused by cutaneous vasodilation (7). This response is transient (30–90 minutes), and accompanied by erythema, tingling, itching, and elevated skin temperature. It is seen at the beginning of nicotinic acid therapy, and tends to subside over time with the development of tolerance. Still, for some it can be disagreeable to the point of discontinuing nicotinic acid treat­ment for hyperlipidemia. The flushing response can be evoked by either oral or topical exposure to nicotinic acid. It appears to be mediated by prostanoids (prostacyclins, prostaglandins) and involves the niacin receptor, which is expressed by macrophages and bone marrow-derived cells of the skin. The response can be minimized by using a slow-release formulation of nicotinic acid, or by using a cyclooxygenase inhibitor (e.g., aspirin, indomethacin) prior to taking nicotinic acid (8). High doses of NA have been reported to cause itch­ing urticaria (hives), and gastrointestinal discom­fort (heartburn, nausea, vomiting, rarely, diarrhoea) in humans. While acute adverse effects of nicotinamide have not been reported for doses used to treat insulin-dependent diabetes (ca. 3 g/day), larger doses (10 g/day) have been found to cause hepatic damage.

Sources of Niacin

Niacin occurs in greatest quantities in brewers’ yeasts and meats, but significant amounts are also found in many other foods. The vitamin is distributed unevenly in grains, being present mostly in the bran frac­tions. Niacin occurs predominantly in bound forms, e.g., in plants mostly as protein-bound nicotinic acid (NA), and in animal tissues mostly as nicotinamide (NAm), nicotinamide-adenine dinucleotide (NAD) and nicotina­mide-adenine dinucleotide phosphate (NADP). Niacin is added by law to wheat flour and other grain products in the United States. Niacin in foods is very stable to storage and to normal means of food preparation and cooking (e.g., moist heat).

Niacin is found in many types of foods in forms from which it is not released on digestion, thus rendering it unavailable to the eater. In grains, niacin is present, bound in complexes with small peptides and car­bohydrates, collectively referred to as niacytin. The niacin in these complexes is not normally available; however, its bioavailability can be improved substantially by treatment with an alkali. Hence, the tradition in Central American cuisine of soaking and cooking maize in lime-water effectively renders available the niacin in that grain. This practice appears to be responsible for effective protection against pellagra in that part of the world. In other foods, niacin is present as a methylated derivative (1-methylnicotinic acid) that functions as a plant hormone but is also not biologically available to animals. This form, however, is heat labile, and can be converted to NA by heating.

FUNCTIONS OF NIACIN

Niacin functions metabolically as the essential component of the enzyme co-substrates NAD(H) and NADP(H). Each acts as an intermediate in most of the hydrogen transfers in metabolism, including more than 200 reactions in the metabolism of carbohydrates, fatty acids, and amino acids according to the general reaction:

Despite their similarities of mechanism and structure, NAD(H) and NADP(H) have quite different metabolic roles, and most dehydrogenases have specificity for one or the other. NAD functions as a hydrogen donor to the mito­chondrial respiratory chain (TCA cycle) for ATP produc­tion. The phosphorylation of NAD facilitates NADP(H) to serve as a co-dehydrogenase in the oxidation of physiological fuels. These reactions involve reductive biosyntheses, such as those of fatty acids and steroids. NAD(H) functions in the polymerases (PARPs), which are activated by DNA single-strand breaks and, thus, serve as a DNA damage sensor. Niacin has been associated with a number of health effects unrelated to the signs of niacin deficiency (9).

Cardiovascular Health/cholesterol

High doses of nicotininc acid have been used in treating hyperlipidemia, reducing all major lipids and apolipoprotein B-containing lipoproteins (VLDL, LDL), and increasing apolipopro­tein A1-containing lipoproteins (HDL) (10-12). It does this in 3 ways:-

Reducing hepatic triglyceride synthesis. Studies have shown that NA can non-competitively limit the amount of triglycerides available for the assembly of VLDL. This results in increased degrada­tion of apolipoprotein B, and the consequent reduction in both VLDL and its catabolic product, LDL (13).

Reducing the removal of HDL apolipoprotein A1. Studies in cultured cells have shown nicotinic acid to inhibit the catabolism of HDL-apo A1 without affecting apo A1 synthesis. This results in increases in HDL and HDL cholesterol. These increases are thought to reflect reduced exchange of triglycerides and cholesterol esters, and the retarded degradation of apolipoprotein A1.

Reducing adipocyte lipolysis. Nicotinic acid can also bind to the niacin receptor and which inhibits reduces the mobilization of fatty acids from triglycerides in adipose tissue. Reduced release of fatty acids is responsible for at least part of the reduction of hepatic synthesis and secretion of VLDLs, and the subsequent decline in circulating LDL levels. Decreased circulating levels of VLDLs are associated with decreased levels of triglycerides and cholesterol (14).

High doses of nicotinic acid have proven to be among the most use­ful treatments for hypercholesterolemia; extended-release formulations of nicotinic acid are effective and offer advantages of less frequently causing flushing. A retrospective evaluation of results from the US Coronary Drug Project showed NA treatment to have reduced antihyperlipidemic effects provide the basis of current interest in nicotinic acid in the prophy­laxis of coronary artery lethal coronary events, resulting in highly significant reduction of mortality from all causes by 11% (vs. a placebo). A meta-analysis of 11 clinical trials with more than 6,600 patients found positive effects of NA, when given alone or in combination with statins, on cardiovascu­lar events (15).

High-dose NA has been shown to reduce blood pressure in hypertensive sub­jects, probably due to vasodilation; however it is not clear whether chronic treatment may have similar effects, as the results of clinical trials have been inconsistent.

Skin Health

Niacin supplementation has been shown to protect skin from DNA-damaging agents in animal models.

Lung Health

Niacin treatment has been shown to reduce lung injury and fibrosis in animal models, including treatment with DNA-damaging agents and exposure to hyperoxic conditions which promote oxidative stress.

Psychological Disorders

Nicotinamide has been shown to enhance the effect of tryptophan in supporting brain serotonin levels. It does so by reducing the urinary excretion of tryptophan metabolites and reduc­ing the conversion of tryptophan to niacin. This increases the availability of tryptophan for the synthesis of sero­tonin, the general effect of which is antidepressive. High doses of nicotinic acid have been found to benefit patients with cer­tain psychological disorders:

Schizophrenia

Schizophrenia is associated with NAD-deficiency in criti­cal areas of the brain. Affected individuals have been found to oxidize nicotinamide more readily than unaffected peo­ple: it has been suggested that schizophrenics suffer a depletion of nicotinamidem which limits NAD synthesis. Patients with first-episode schizophrenia can show diminished flushing responses to niacin. This response is mediated by vasodilators derived from arachidonic acid, which levels are typically low in such patients. High doses of NA (e.g., 1 g/day) given with ascorbic acid have been found to elimi­nate psychotic symptoms and prevent relapses of acute schizophrenics (16).

Hartnup Disease

This is a rare familial disorder involving malabsorption of tryptophan (and other amino acids). It is characterized by a pellagra-like skin rash (pre­cipitated by psychological stress, sunlight or fever), and neurological changes including attacks of ataxia and psy­chiatric disorders ranging from emotional instability to delirium. Patients appear to have abnormally low capaci­ties to convert tryptophan to niacin, apparently resulting from reduced enteric absorption and renal reabsorption of tryptophan. Non-reabsorbed tryptophan appears to be degraded by microbial tryptophanase to pyruvate and indole, the latter of which is reabsorbed from the intestine and is neuro­toxic. Patients respond to treatment with NA.

Depression

Patients with depressive symptoms can show diminished flushing responses to niacin. Studies have shown that some 5% of depressive subjects do not show the niacin-induced flushing; recent studies suggest that the non-responders are likely to be severely ill, with depressed mood, anxiety, feelings of guilt, and physical symptoms (17).

Diabetes

Diabetes is associated with a reduced state of the pyri­dine nucleotides in the cytosol and mitochondria due to the increased levels of glucose, FFA, lactate, and branched-chain amino acids (18). In clinical trials, nicotinamide has been found to protect high-risk children from developing clinically apparent insu­lin-dependent diabetes, and to improve small artery vasodilatory function in statin-treated type 2 diabetic patients (19,20).

Foetal Alcohol Syndrome

Studies in animal models have demonstrated benefits of nicotinamide treatment in reducing anxiety and preventing neural damage in progeny of alcohol-treated dams (21,22).

 

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Keywords-niacin, pellagra, cardiovascular health, cholesterol, niacin flushing, skin, lung, schizophrenia, depression, diabetes, pregnancy, anaemia