Niacin is a collective term for chemical structures of the pyridine-3-carboxylic acid, which includes nicotinic acid, its acid amide nicotinamide, and the biologically active coenzymes nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). The earlier designation of vitamin B3 as “PP factor” (pellagra preventing factor) or “pellagra protective factor” goes back to the discovery by Goldberger in 1920 that pellagra is a deficiency disease and is due to the absence of a dietary factor in corn. It was not until many years later that experimental studies provided evidence that pellagra could be eliminated by niacin. Nicotinamide is found preferentially in the animal organism in the form of the coenzymes NAD and NADP. Nicotinic acid, on the other hand, is found primarily in plant tissues, such as cereals and coffee beans, but in smaller amounts and there it is mainly covalently bound (by means of a fixed atomic bond) to macromolecules – niacytin, a form that cannot be utilized by the human organism. Nicotinic acid and nicotinamide are interconvertible in intermediate metabolism and coenzymatically active in the form of NAD and NADP, respectively.
Synthesis
The human organism can produce NAD in three different ways. The starting products for NAD synthesis are nicotinic acid and nicotinamide, in addition to the essential (vital) amino acid tryptophan. The individual synthesis steps are shown as follows. NAD synthesis from L-tryptophan.
- L-tryptophan → formylkynurenine → kynurenine → 3-hydroxykynurenine → 3-hydroxyanthranilic acid → 2-amino-3-carboxymuconic acid semialdehyde → quinolinic acid.
- Quinolinic acid + PRPP (phosphoribosyl pyrophosphate) → quinolinic acid ribonucleotide + PP (pyrophosphate).
- Quinolinic acid ribonucleotide → nicotinic acid ribonucleotide + CO2 (carbon dioxide).
- Nicotinic acid binucleotide + ATP (adenosine triphosphate) → nicotinic acid dinucleotide + PP
- Nicotinic acid adenine dinucleotide + glutaminate + ATP → NAD + glutamate + AMP (adenosine monophosphate) + PP
NAD synthesis from nicotinic acid (Preiss-Handler pathway).
- Nicotinic acid + PRPP → nicotinic acid ribonucleotide + PP.
- Nicotinic acid ribonucleotide + ATP → nicotinic acid adenine dinucleotide + PP
- Nicotinic acid adenine dinucleotide + glutaminate + ATP → NAD + glutamate + AMP + PP
NAD synthesis from nicotinamide
- Nicotinamide + PRPP → nicotinamide ribonucleotide + PP
- Nicotinamide ribonucleotide + ATP → NAD + PP
NAD is converted to NADP by phosphorylation (attachment of a phosphate group) using ATP and NAD kinase.
- NAD+ + ATP → NADP+ + ADP (adenosine diphosphate).
NAD synthesis from L-tryptophan plays a role only in the liver and kidney. Thereby, 60 mg of L-tryptophan are equivalent (equivalent) to one milligram of nicotinamide in humans on average. Vitamin B3 requirements are therefore expressed in niacin equivalents (1 niacin equivalent (NE) = 1 mg niacin = 60 mg L-tryptophan). However, this ratio does not apply in tryptophan-deficient diets because protein biosynthesis is limited (restricted) when tryptophan intake is low, and the essential amino acid is used exclusively for protein biosynthesis (new protein formation) until an excess over the requirement for protein biosynthesis enables NAD synthesis [1-3, 7, 8, 11, 13]. Accordingly, adequate tryptophan intake should be ensured. Good sources of tryptophan are mainly meat, fish, cheese and eggs as well as nuts and legumes. In addition, an adequate supply of folate, riboflavin (vitamin B2), and pyridoxine (vitamin B6) is important because these vitamins are involved in tryptophan metabolism. The quality and quantity of protein consumption as well as the fatty acid pattern also influence the synthesis of niacin from L-tryptophan. While the conversion of tryptophan to NAD increases with an increase in the intake of unsaturated fatty acids, the conversion rate (rate of conversion) decreases with an increase in the amount of protein (> 30%). In particular, an excess of the amino acid leucine causes disturbances in tryptophan or niacin metabolism, because leucine inhibits both the cellular uptake of tryptophan and the activity of quinolinic acid phosphoribosyl transferase and thus NAD synthesis. Conventional corn is characterized by a high leucine and low tryptophan content.Breeding improvements have made it possible to produce the Opaque-2 corn variety, which has a relatively high protein and tryptophan concentration and a low leucine content. In this way, the occurrence of vitamin B3 deficiency symptoms can be prevented in countries where corn is a staple food, such as Mexico. Finally, the endogenous (body’s own) synthesis of niacin from L-tryptophan varies depending on the quality of the diet. Despite an average conversion of 60 mg tryptophan to 1 mg niacin, the fluctuation range is between 34 and 86 mg tryptophan. Accordingly, no precise data are available on the self-production of vitamin B3 from tryptophan.
Absorption
Nicotinamide is rapidly and almost completely absorbed (taken up) as free nicotinic acid after breakdown of coenzymes already in the stomach, but for the most part in the upper small intestine after bacterial hydrolysis (cleavage by reaction with water). Intestinal absorption (uptake via the intestine) into mucosa cells (mucosal cells) follows a dose-dependent dual transport mechanism. Low doses of niacin are actively absorbed (taken up) by means of a carrier following saturation kinetics in response to a sodium gradient, while high doses of niacin (3-4 g) are additionally absorbed (taken up) by passive diffusion. Absorption of free nicotinic acid also occurs rapidly and almost completely in the upper small intestine by the same mechanism. The absorption rate of niacin is mainly influenced by the food matrix (nature of food). Thus, in animal foods, absorption of almost 100% is found, while in cereal products and other foods of plant origin, due to the covalent binding of nicotinic acid to macromolecules – niacytin – bioavailability of only about 30% can be expected. Certain measures, such as alkali treatment (treatment with alkali metals or chemical elements, such as sodium, potassium and calcium) or roasting of the corresponding foods, can cleave the complex compound niacytin and increase the proportion of free nicotinic acid, resulting in a significantly increased biological usability of nicotinic acid. In countries where corn is the major source of niacin, such as Mexico, pretreatment of corn with calcium hydroxide solution provides a staple food that contributes significantly to meeting niacin requirements. Roasting coffee demethylates the methylnicotinic acid (trigonelline) contained in green coffee beans, which is not usable by humans, increasing the free nicotinic acid content from previously 2 mg/100 g of green coffee beans to about 40 mg/100 g of roasted coffee. Concurrent dietary intake has no effect on the absorption of nicotinic acid and nicotinamide.
Transport and distribution in the body
Absorbed niacin, mainly as nicotinic acid, enters the liver via the portal blood, where conversion to the coenzymes NAD and NADP occurs [2-4, 7, 11]. In addition to the liver, erythrocytes (red blood cells) and other tissues are also involved in the storage of niacin in the form of NAD(P). However, the reserve capacity of vitamin B3 is limited and is about 2-6 weeks in adults. The liver regulates the NAD content in tissues depending on the extracellular (located outside the cell) nicotinamide concentration – when needed, it breaks down NAD to nicotinamide, which serves to supply the other tissues in the bloodstream. Vitamin B3 has a pronounced first-pass metabolism (conversion of a substance during its first passage through the liver), so that in the low dose range nicotinamide is released from the liver into the systemic circulation only in the form of the coenzymes NAD and/or NADP. In experiments in rats, it was found that after intraperitoneal administration (administration of a substance into the abdominal cavity) of 5 mg/kg body weight of labeled nicotinic acid, only a small portion appears unchanged in the urine. After high doses (500 mg niacin) or under steady-state conditions (oral dose of 3 g niacin/day), on the other hand, more than 88% of the administered dose was found in unchanged and metabolized (metabolized) form in the urine, suggesting almost complete absorption.Nicotinic acid, unlike nicotinamide, cannot cross the blood–brain barrier (physiological barrier between the bloodstream and the central nervous system) and must first be converted to nicotinamide via NAD to do so.
Excretion
Under physiological conditions, niacin is mainly excreted as:
- N1-methyl-6-pyridone-3-carboxamide.
- N1-methyl-nicotinamide and
- N1-methyl-4-pyridone-3-carboxamide eliminated by the kidney.
After higher doses (3 g vitamin B3/day), the excretion pattern of metabolites (degradation products) changes so that primarily:
- N1-methyl-4-pyridone-3-carboxamide,
- Nicotinamide-N2-oxide, and
- Unchanged nicotinamide appear in the urine.
Under basal conditions, humans excrete about 3 mg of methylated metabolites daily through the kidney. In deficient (deficient) vitamin B3 intake, renal elimination (excretion via the kidney) of pyridone decreases earlier than that of methyl nicotinamide. While an excretion of N1-methyl-nicotinamide of 17.5-5.8 µmol/day indicates borderline niacin status, an elimination < 5.8 µmol N1-methyl-nicotinamide/day is an indicator of vitamin B3 deficiency. The elimination or plasma half-life (time elapsing between the maximum concentration of a substance in blood plasma to the fall to half this value) depends on the niacin status and the dose supplied. It averages about 1 hour. Chronic dialysis treatment (blood purification procedure) used in patients with chronic renal failure may result in appreciable losses of niacin and, therefore, lower serum nicotinamide levels.
