20.1: Niacin - Introduction (20c.1)

Niacin (also known as "vitamin B3") is the term used to describe a group of compounds with the biological activity of the vitamin. They include nico­tinic acid (also known as niacin) composed of a pyrimidine ring bound to a carboxylic group (pyridine-3-carboxylic acid), nico­tin­amide (also known as niacinamide) composed of a pyrimidine ring bound to a carbox­amide group (pyridine-3-carbox­amide), and nico­tin­amide riboside. The third compound, nico­tin­amide riboside has been identified more recently and is a pyridine-nucleoside form of vitamin B3 consisting of nico­tin­amide with a beta-D-ribofuranosyl moiety at the 1‑position (Mehmel et al., 2020). All three compounds have similar but not identical properties and are precursors of nico­tin­amide adenine dinucleo­tide (NAD) and its phos­phory­lated derivative, nico­tin­amide adenine dinucleo­tide phosphate (NADP). The structures of nico­tinic acid, nico­tin­amide, and nico­tin­amide riboside are shown in Figure 20c.1.

Figure 20c.1. Vitamin B3 molecules (nico­tinic acid, nico­tin­amide, and nico­tin­amide riboside), dietary precursors that support the form­ation of nicotinamide adenine dinucleotide. Redrawn from Kirkland & Meyer-Ficca (2018).

20c.1.1 Functions of niacin

Most of the niacin in food is present as NAD and NADP; very little exists as free forms of niacin (Chungchunlam & Moughan, 2023). Prior to absorp­tion, these two com­ponents must first be hydro­lyzed to free nico­tin­amide by phos­phatases and NAD glyco­hydro­lases in the small intestine, the major site of absorp­tion. At low intakes, absorp­tion into the intestinal cell is by sodium-dependent, carrier-mediated diffusion, but at higher intakes, passive diffusion predom­inates (Hrubša et al., 2022). Once absorbed, free nico­tin­amide is trans­ported to all tissues for the synthesis of the two coen­zymes NAD and NADP within the cells. In general, concentrations of intra­cellular NAD are higher than NADP. All tissues of the body can syn­the­size NAD and NADP, although concentrations are greatest in the liver where some storage may occur. Some niacin can be syn­the­sized by colonic bacteria in the large intestine (Yoshii et al., 2019). NAD exists in two forms: NAD+ (oxidized) and NADH (reduced), while NADP exists as NADP+ (oxidized) and NADPH (reduced).

NAD+ can be syn­the­sized within the cell from nico­tinic acid, nico­tin­amide, nico­tin­amide riboside, and tryp­to­phan by three path­ways, all of which require the enzyme nico­tin­amide mono­nucleotide phosphoribosyl­transferase (NMNAT). The three path­ways include the con­ver­sion of tryp­to­phan to NAD via the de novo NAD synthesis path­way, the Preiss-Handler path­way from nico­tinic acid, comprising three individual metabolic conversions, and the salvage path­way involving the NAD+ precursors nico­tin­amide or nico­tin­amide riboside. Of the three, the salvage path­way is the domi­nant one; for more details on these synthetic path­ways see Kirkland & Meyer-Ficca (2018).

NAD+ primarily participates in cata­bolic reactions and is an essential substrate for the activity of three classes of NAD+ -consuming enzymes: (i) sirtuins (SIRTs), (ii) poly(ADP-ribose) polymerases (PARPs), and (iii) cyclic ADP-ribose (cADPr) synthases. These NAD+-consuming enzymes cleave NAD+, resulting in an ongoing loss of NAD+ during which nico­tin­amide is produced as a reaction by-product. Because loss of NAD+ cannot be compen­sated by intake of NAD from the diet, nico­tin­amide is recycled into NAD+ via the salvage path­way. This path­way involves the activity of NAMPT and nico­tin­amide mono­nucleotide adenylyl­transferase (NMNAT 1‑3). Hence, activity of these enzymes has a larger effect on NAD concen­trations than nico­tin­amide or dietary intakes of niacin. For more details on the action of these enzymes see Xiao et al. (2018) and Penberthy & Kirkland (2020).

NAD+ can be converted to NAD+phosphate (NADP+) by the activity of NAD+ kinase. NAD(H) can also be utilized as a substrate during which NADPH is produced instead of NADP+, a process involving yet another NAD+-consuming process. During meta­bolism both NAD+ and the phos­phoryl­ated form NAD(P)+ undergo redox reactions and generate two redox couples NAD+ / NAD(H) and NAD(P)+ / NAD(P)H. The NAD+ / NAD(H) redox couple participates in about 400 reactions, predominately in cata­bolic meta­bolism, and regulates cellular energy meta­bolism, that is glycolysis and mitochondrial oxidative phos­phoryl­ation. By contrast, the NADP+ / NAD(P)H pool participates in about 30 reactions, mainly in anabolic meta­bolism, and supports the biosynthesis of fatty acids, nucleic acids and chol­esterol / steroids. It is also involved in maintaining redox balance. For a review of the cata­bolic processes and anabolic processes involving NAD+ and NAD(P)+, see Hrubsa et al. (2022) and Kirkland & Meyer-Ficca (2018) for more details.

Loss of cellular redox homeostasis of NAD+ / NAD(H) has been linked to a variety of patho­log­ical conditions, such as cardio­vascular diseases, neuro­generative diseases, cancer, and aging (Xiao et al., 2018). More research is required to better under­stand the cellular functions of NAD(H) and NADP(H) and how loss of redox homeostasis affects energy meta­bolism.

In addition to its redox roles, NAD+ is also an essential cofactor for important non-redox signaling path­ways, thus regulating biological functions, including gene expres­sion, cell cycle progres­sion, DNA repair and cell death. For more details on the role of NAD in the central nervous system, see Gasperi et al. (2019).

The major path­way of catabolism of nico­tinic acid and nico­tin­amide is by methyl­ation in the liver to N'‑methyl­nico­tin­amide (NMN) and subsequent oxidation to N‑methyl-2‑pyridone-carbox­amide (2‑pyridone) and N'‑methyl-4‑pyridone-5-carbox­amide (4‑pyridone). Under normal conditions, 20‑35% and 45‑60% of niacin is excreted as N'‑methyl­nico­tin­amide (NMN) and 2‑pyridone respectively, although the amount varies depending on niacin and tryp­to­phan intake (EFSA, 2014).

A small percentage of the essential amino acid tryp­to­phan is converted directly to nico­tin­amide adenine dinucleo­tide (NAD) via a two-step path­way (Figure 20c.2), primarily in the liver. The con­ver­sion rate is dependent on the status of tryp­to­phan rather than niacin, and is controlled by the activities of several enzymes; for more details see Fukowatari & Shibata (2013). Low intakes of tryp­to­phan, interference with tryp­to­phan trans­port, as occurs in Hartnup's disease, and conditions associated with increased tryp­to­phan meta­bolism (e.g., inflam­matory bowel diseases) (Nikolaus et al., 2017), all reduce the con­ver­sion of tryp­to­phan to niacin, resulting in an increased need for preformed niacin. Pyridoxal 5‑phosphate (a vitamin B6 derived coen­zyme), iron, riboflavin, ascorbic acid, and glutamine are involved as cofactors in the con­ver­sion of tryp­to­phan to NAD (Penberthy & Kirkland, 2020).

Physiological amounts of both nico­tinic acid and nico­tin­amide prevent the classical signs of niacin deficiency (see section below). However, certain niacin compounds also have pharmacological properties. At supra­physio­logical doses, nico­tinic acid is known to decrease total cholesterol, LDL cholesterol, and triglycerides and increase high-density lipoprotein cholesterol (HDL-C) (Minto et al., 2017). Chronic sup­plement­ation with nico­tin­amide ribose may also have some positive benefits such as reducing blood pressure and arterial stiffness, and warrants further study (Martens et al., 2018). Recent research has also implicated niacin as a therapeutic neuro­protective agent (Gasperi et al., 2019), although more studies are needed to confirm the role of niacin for alleviating neuro­logical impairment (Wuerch et al., 2023). In addition, decline of NAD+ levels during the aging process has led to investigations on the role of niacin in aging-related processes. Results suggest that niacin supple­ments, as the major nutritional precursor of NAD, may provide anti­aging properties (Imai et al., 2014).

20c.1.2 Deficiency of niacin in humans

Pellagra is the characteristic syndrome of severe niacin deficiency and its dietary precursor tryp­to­phan. Pellagra is known as the disease of the "4Ds" (diarrhea, dermatitis, and dementia, culmin­ating in death). Early symptoms include diarrhea resulting from intestinal inflam­mation, accom­panied by anorexia, nausea, and abdominal pain. Later, dermatitis develops in sun-exposed skin such as dorsal parts of hands, feet, cheeks, forehead, and sun-exposed regions of the neck (WHO, 2000). These signs arise from deficits in poly (ADP-ribose) polym­erase activity in response to UV radiation-induced DNA damage. The third D refers to dementia and presents with hallucinations and delusions, symptoms said to be caused by impaired form­ation of cADP-ribose and nico­tinic acid ADP, which result in alterations in neural calcium signaling (Meyer-Ficca & Kirkland, 2016).

Migraine, a neuro­logical condition related to brain energy deficiency, has recently been associated with intakes of dietary niacin in a population-based study of US adults (>20y) participating in NHANES 1999-2004 (Liu et al., 2022). An L-shaped relationship between dietary niacin intake and migraine was reported, with the risk decreasing with increasing dietary niacin consumption in those with a dietary niacin intake of <21.0mg/d. However, there was no association between dietary niacin consumption and migraine when the daily niacin intake was >21.0mg/d, indicating that the risk of migraine no longer decreases with increasing dietary niacin intake (Liu et al., 2022). A few case reports have also suggested that niacin may be effective as an adjuvant treat­ment for acute migraine, although the underlying mechanism is uncertain.

Pellagra is often a problem in countries where maize and millet jowar (Sorghum vulgare) are dietary staples. The bio­avail­ability of niacin in maize is poor (only about 30%) because most of the niacin is present in two forms: niacytin and niacino­genes. Niacytin consists of nicotinic acid esterified to poly­saccharides, whereas niacino­genes are bound to poly­peptides and glyco­peptides; both forms are unavailable for absorp­tion by intestinal enzymes. Maize is also particularly low in tryp­to­phan, a precursor of NAD (WHO, 2000). In contrast, millet jowar contains suitable amounts of tryp­to­phan, but excessive amounts of leucine which inter­fere with the con­ver­sion of tryp­to­phan to niacin. The mechanism is uncertain. Excess leucine may disrupt the availability or utilization of riboflavin and vitamin B6, micronutrients required in the synthesis of niacin from tryp­to­phan (Kirkland & Meyer-Ficca, 2018).

Niacin fortification of cereals, notably maize, has been associated with wide­spread reductions in the preval­ence of pellagra (Vilijoen et al., 2022). Never­the­less, out­breaks of pellagra still occur where cereals are not fortified and diets are restricted. Such outbreaks have been reported in Malawi among Mozambican refugees (Malfait et al., 1993), and more recently, among adults in the Kasese Catchment Area, Dowa, Malawi (Matapandeu et al., 2017).

Secondary pellagra can develop from certain diseases or conditions that inter­fere with the absorp­tion of niacin or tryp­to­phan or reduce the con­ver­sion of tryp­to­phan to niacin. Diseases that inter­fere with absorp­tion may include chronic diarrhea, chronic colitis, cirrhosis of the liver, and tuberculosis of the gastro­intestinal tract (Prabhu et al., 2021). Chronic alcoholism causes a reduction in the con­ver­sion of tryp­to­phan to niacin, arising from inhibition of tryp­to­phan 2,3-dioxygenase, a rate-limiting enzyme of the hepatic kynurenine path­way of tryp­to­phan degrad­ation and niacin synthesis (Prabhu et al., 2021). Even in countries with niacin fortification of wheat flour such as the United States, alcohol-associated pellagra cases have been reported. Other diseases in which the con­ver­sion of tryp­to­phan to niacin is reduced include the genetic disorder Hartnup disease when there is a deficit in tryp­to­phan trans­port (Kirkland & Meyer-Ficca, 2018) and carcinoid syndrome in which tryp­to­phan is preferentially oxidized to 5‑hydroxy­tryptophan and serotonin (Gade et al., 2020).

Prolonged treat­ment of tuberculosis with the drug isoniazid also reduces the con­ver­sion of tryp­to­phan to niacin by competing with pyridoxal 5'‑phosphate (a vitamin B6 derived coen­zyme required in the tryp­to­phan-to-niacin path­way). In Malawi, an increased risk of pellagra has been associated with mass scale-up of isoniazid use for the preventive treat­ment of tuberculosis for people living with HIV. Continuous isoniazid preventive treat­ment for tuber­culosis and the annual period of food scarcity were reported to increase the risk in this matched case-control study (Nabity et al., 2022). Such findings indicate that co‑administration of niacin-containing multi‑B vitamins with isoniazid as a pellagra prevention, warrants exploration.

20c.1.3 Food sources and dietary intakes

Most of the niacin in food is present as a component of NAD or NADP as noted earlier; very little exists as free forms of niacin, with the exception of liver and beans. Rich food sources of niacin include meat (especially liver), poultry, and fish followed by dairy products, oilseeds, some cereals (especially when enriched or fortified with niacin), legumes (including peanuts) and baker's yeast (Hrubša et al., 2022). In milk, 40% of the niacin is present as nico­tin­amide riboside and 60% as nico­tin­amide (Bieganowski & Brenner, 2004). Animal products release nico­tin­amide from its nucleotide forms during food pro­ces­sing and digestion, whereas plant products largely deliver nico­tinic acid. Tea, coffee, and cocoa beverages also contains an appreciable amount of niacin.

Absorption of niacin from food ranges from about 23% to 70% and is lowest from cereals and highest from animal products (EFSA, 2014). Certain food preparation and pro­ces­sing methods can influence the content and bio­avail­ability of niacin in food. Milling of cereals reduces their niacin content. Treat­ment of cereals with alkali (e.g., lime water), baking with alkaline baking powders, and roasting whole grain maize, all increase niacin bio­avail­ability by releasing the bound forms of niacin. The thermo-alkaline pro­ces­sing of maize kernels termed "nix­tamaliz­ation" and practiced in Latin America, is responsible, at least in part for the very low preval­ence of pellagra in the region (Hrubša et al., 2022). Roasting green coffee also increases its nico­tinic acid content, by removing the methyl group from trigonelline (N'‑methyl­nico­tinic acid) (Hrubša et al., 2022). The coffee cultivar, degree of roasting, and brewing techniques all influence the amount of nico­tinic acid in a cup of coffee. Although resistant to high tem­per­atures, significant amounts of water-soluble niacin can be lost in cooking water, if discarded. More details of the content and bio­avail­ability of niacin in both animal and plant-based foods are available in Chungchunlam & Maughan (2023).

In industrialized countries, meat and meat products often contribute as much as one third of the total intake of niacin of adults, closely followed by enriched or fortified cereals, whole-grain breads and bread products, and fortified ready-to-eat cereals; vegetables and milk + milk products contribute about one-tenth of the total niacin intake (Gregory et al., 1990; McLennan and Podger, 1995; IOM, 1998; EFSA, 2014).

Because niacin can be derived from the amino acid L-tryp­to­phan, a precursor of niacin, intakes are usually expressed in terms of niacin equivalents (NE). About 60mg of tryp­to­phan yields 1mg niacin following digestion and absorp­tion. However, the con­ver­sion rate varies widely (30%) between individuals and tends to increase with increased tryp­to­phan consumption. The most common sources of tryp­to­phan in U.S diets are high protein foods such as fish, chicken, and milk, as well as bananas, chocolate, and peanuts (Richard et al., 2009). Conversion of niacin from tryp­to­phan does not meet the need for niacin, of which about 50% is provided by dietary niacin sources. In Europe in 2014, the average daily intakes of total niacin from nine countries ranged from 27 to 53mg NE/day, with those for males slightly higher than females due mainly to the larger quantities of food consumed(EFSA, 2014). A summary table of the niacin intakes in these nine European countries is available in ESFA (2014).

In the United States, the Dietary Reference Intakes (DRIs) are set by the Institute of Medicine (IOM, 2000). The Estimated Average Requirements (EARs) are 12mg NE/day and 11mg NE/day, respec­tively for male and female adults. Corres­ponding levels for the US Recommended Dietary Allowances (RDAs) are 16mg NE/day for males and 14mg NE/day for females. Both male and female RDA intake levels for adults are similar to the Recommended Nutrient Intakes (RNIs) set by WHO/FAO (2004). In contrast, EFSA (2014) have set the Dietary Reference Values (DRVs) for niacin based on the relationship between niacin require­ment and energy require­ment. The Average Requirement (i.e., EAR) for adults (both men and women) is set at 1.3mg NE/MJ (about 5.5mg NE/1000kcal) and the Population Reference Intake (i.e. the RDA & RNI) corresponds to 1.3mg NE/MJ (about 6.6mg NE/1000kcal) assuming a coefficient of variation of 10%. These are the same levels set by the Scientific Committee for Food (SCF) in 1993. For details of the DRVs for other age and life-style groups set by these agencies, see relevant publications.

20c.1.4 Effects of high intakes of niacin

Niacin toxicity may occur when large pharmacological doses of different forms of niacin, especially nico­tinic acid, are taken to prevent or treat some metabolic diseases, as noted earlier. For example, nico­tinic acid is used in high doses (>1000mg/d) to treat hyper­lipidemia but is sometimes accom­panied by side effects. Of these, facial flushing caused by prostaglandin D2-mediated vaso­di­latation of small sub­cutaneous blood vessels, may occur, and has even been reported at doses of nico­tinic acid below 50mg/d (MacKay et al., 2012).

Most agencies use dermal vaso­dilative flushing as the basis of their Tolerable Upper Intake Levels (ULs) for niacin compounds. The U.S. Food and Nutrition Board (IOM, 2000) have set the Tolerable Upper Intake Level (UL) for adults at 35mg/d for all forms of "niacin", whereas both Europe and the United Kingdom have set different ULs for free nicotinic acid and nico­tin­amide because nico­tin­amide does not produce vaso­dilative flushing but has no beneficial effects on lipid profiles (Minto et al., 2017). For free nico­tinic acid and nico­tin­amide, the ULs for adults set by the European Food Safety Authority (ESFA) are 10mg/d and 900mg/d, respec­tively (EFSA, 2014), and 17mg/d and 500mg/d, respect­ively for the UK Safe Upper Levels (SULs)(Food Standard Agency, 2003). Differ­ences in the methods used by these agencies to set the ULs may account in part for these dis­crep­ancies (Minto et al., 2017). There is some concern about whether the flushing effect is an appro­priate basis for the UL for nico­tinic acid (MacKay et al., 2012), and whether different ULs should be set for healthy and unhealthy persons (Minto et al., 2017). Note: the UL does not apply to persons taking high-dose niacin for treat­ment of dyslipidemia.