HISTORY, STRUCTURE, CHEMISTRY, DIETARY SOURCES, DISTRIBUTION AND ABSORPTION, UTILISATION, TRANSPORT, METABOLISM, STORAGE
FUNCTIONS, DEFICIENCY OF NIACIN
8.15 INTRODUCTION
Students, you must have used the terms B complex vitamins often in your daily life. You might be wondering why we need to learn about these. What is its role in our body? It is important for us to gain a good understanding of this nutrient in terms of its chemical structure, biological role, deficiency and toxicity. Let us start with introduction
Vitamin B3 (Niacin) is used commonly to refer to two different compounds, nicotinic acid and niacinamide. B3 was first isolated during oxidation of nicotine from tobacco and was thus given the name nicotinic acid. Later the name 'niacin' was derived from nicotinic acid + vitamin.Vitamin B3 is also referred to as "vitamin PP," a name derived from the obsolete term
"pellagra-preventing factor."this vitamin was once called the anti-black tongue factor because of its effect in dogs.
Niacin is one of the water soluble B-vitamins. In 1735 a Spanish physician, Casals described a disease called pellagra a term of Italian origin meaning rough skin. In 1915 Goldberger conducted an experiment on twelve prisoners and fed a diet consisted of sweet potatoes, corn bread, cabbage, rice, corn grits, syrup, sugar, biscuits and black coffee. After a few weeks the prisoners developed headache, abdominal pain and general weakness and in about 5 months the typical dermatitis of pellagra appeared. Goldberger in 1914 suggested the existence of pellagra–preventing (PP) factor and related it to B–vitamins through epidemiological and experimental work. Nicotinic acid was isolated as a pure chemical substance in 1867; however in 1937 Elvehjem demonstrated that the vitamin can cure both pellagra in humans and black tongue in dogs.
In the blood, brain, kidney and liver it is converted to the coenzymes nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP), both of
which are involved in the generation of energy in cells. Tryptophan is an amino acid which is a provitamin of niacin.
8.15 .1 OBJECTIVES
After studying this unit you will be able to understand
the structures and chemical characteristics of niacin
functions of niacin
the digestion , absorption and metabolism
food sources
the deficiency symptoms of niacin
8.15 .2 STRUCTURE
Niacin (Vitamin B3) is considered a Generic term for nicotinic acid and nicotinamide (also called niacinamide). Structurally, nicotinic acid is pyridine 3-carboxylic acid, while nicotinamide is nicotinic acid amide. The vitamin activity of niacin is provided by both nicotinic acid and nicotinamide
8.15 .2 CHEMISTRY AND CHARACTERISTICS
Nicotinic acid and niacin amide with the formula C6H5NO2 are organic compounds of relatively simple structure with equal biological activity. The two forms are white bitter tasting compounds, moderately soluble in hot water but only slightly soluble in cold water. Niacin is
very stable to alkali, acid, heat, light and oxidation even boiling and auto calving do not decrease its potency. This water-soluble solid is a derivative of pyridine, with a carboxyl group (COOH) at the 3-position. Other forms of vitamin B3 include the corresponding amidenicotinamide ("niacinamide"), where the carboxyl group has been replaced by a carboxamide group(CONH2), as well as more complex amides and a variety of esters. Niacin and niacinamide are both readily absorbed from the small intestine.
8.15 .3 DIETARY SOURCES
Diet that furnishes sufficient amount of protein provides enough niacin ie protein supplies tryptophan for conversion to niacin. Animal proteins contain about 1.4 percent protein and plant sources about 1 percent protein. Assuming that a mixed diet provides 1% of the protein as tryptophan, than an intake of 65g protein is equivalent to 650 mg tryptophan or 10.8mg niacin.
In animals niacin is present as nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). However after the slaughter of animals, nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP) undergo hydrolysis, resulting in meat providing niacin as free nicotinamide. Poultry, meat and fish are the most important sources of niacin organ meats, peanuts, peanut butter and brewer’s yeast are rich sources.
Whole grains are fair sources of niacin but most of this is in bound form which may not be completely available.
Potatoes legumes and some green leafy vegetables contain fair amounts of preformed niacin but most fruits and vegetables are poor sources. Milk and milk products are also poor sources.
8.15 .4 DIGESTION, ABSORPTIONAND TRANSPORTATION
The digestion of niacin involves conversion of nicotinamide adenine dinucleotide (NAD) to nicotinamide ribonucleotide (NMN) in presence of intestinal pyrophosphatase and
nicotinamide by NAD glycohydrase. Nicotine acid and its amide are readily absorbed by sodium-dependent facilitated diffusion or passive diffusion in the stomach and small intestine.
However tissue uptake of Nicotine acid and nicotamide is by simple diffusion, metabolic trapping as nucleotides in erythrocytes is through facilitated diffusion. Concentration of vitamin in the lumen of the intestine, however, appears to determine its mode of absorption. At low concentrations niacin is absorbed almost completely by passive diffusion. In the plasma, niacin is found primarily as nicotamide, but nicotinic acid also may be found. Up to about one-third of nicotinic acid in the plasma is bound to plasma proteins. From the blood, nicotamide and nicotinic acid move across cell membranes by simple diffusion; however, nicotinic acid transport into the kidney tubules and red blood cells requires carrier.
8.15 .5 METABOISM AND EXCRETION
NAD, generated from nicotinamide or produced in the liver from tryphtophan, and NDAP can be degraded by glycohydrolase into nicotinamide and ADP-ribose. The released Nicotamideis methylated and is then oxidized in the liver into many metabolitessuch as N’methylnicotnamide, N’methyl 2-pyridone 5-carboxamide, N’methyl 4-pyridone carboxamide, etcthat are excreted in the urine in small amounts. Nicotinic acid and nicotamide is excereted in small amounts as both the compounds may be actively reabsorbed from glomerular filtrate.
8.15 .6 STORAGE AND DISTRIBUTION
Niacin is readily absorbed from the small intestine. Vitamin is trapped within the cell as NAD or NADP. Some small reserves are available in the body in liver and day to day supply is desirable. In the liver, excess niacin and tryptophan are converted to NAD and stored in small amounts not bound to enzymes. NAD may be degraded to yield nicotinamide, which then is available for transport to other tissues. NAD is found primarily in its oxidized form NAD+, while NADP is found in cells mainly in its reduced form NADPH. Any excess get excreted in the urine. Tryptophan, one of the essential amino acids is a precursor of niacin so that a diet that contains a liberal amount of tryptophan will provide enough niacin even though the diet is low in niacin.
8.15 .7 FUNCTIONS
We know that approximately 200 enzymes, primarily dehydrogenases, require the coenzymes NAD and NADP, which act as a hydrogen donor or electron acceptor. They are therefore key components of many metabolic pathways. Niacin functions as a substrate in nonredox roles as a donor of adenosine diphosphate ribose (ADP-ribose). Both nicotinic acid and nicotinamide are very similar and undergo reversible reduction in similar way; however their functions in the cell are quite different.
The major role of NADH is to transfer its electrons from metabolic intermediates through the electron transport chain thereby producing adenosine triphosphate (ATP). NADPH acts as a reducing agent in many biosynthetic pathways. NAD and NADP are tightly bound to their apoenzymes and can easily transport hydrogen atoms from one part of the cell to another. These reactions occur in the mitochondria and the cytoplasm.
NAD+ and NADP+ functions as coenzymes in several oxidation –reduction reactions.
Generally NAD+ linked dehydrogenase catalyze oxido-reduction in oxidative pathways, while NADP+ linked dehydrogenases or reductases are often found in pathways concerned with synthesis.
Oxidative reactions in which NAD participates and is reduced to NADH are-
Glycolysis
Oxidative decarboxylation of pyruvate
Oxidatation of acetyl CoA in the TCA cycle
Β-oxidation of fatty acids
Oxidation of ethanol
NAD is required for catabolism of Vitamin B6 as pyridoxal to its excretory product, pyridoxic acid.
NADPH is genetrated from NADP by reduction which occurs as part of the hexose monophosphate shunt by the mitochondrial. This NADPH produced in used in some reductive biosynthesis, such as –
Fatty acid synthesis
Cholesterol and steroid hormone synthesis
Oxidation of glutamate
Synthesis of deoxyribonucleotides (precursors of DNA)
Regeneration of glutathione, vitamin C, NAD thioredoxin
Conversion of folate to active forms- dihydrofolate (DHF) and tetrahydrofolate (THF)
Suthesis of 5-methyl tetrahydrofolate and 5,10-methlene tetrahydrofolate The other functions are
Niacin is essential for the manufacture of enzymes that provide cells with energy. These enzymes are nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP).Niacin is involved in reactions that generate energy in tissues by the biochemical conversion of carbohydrates, fats, and proteins.
Niacin is essential for growth and is involved in the synthesis of hormones. Niacin is absorbed in the intestine and stored in the liver. Excessive niacin is excreted in the urine.
Helps synthesize DNA.
Niacin is essential for healthy skin, tongue and digestive tract tissues and the formation of red blood cells.
It helps in normal secretion of bile and stomach fluids.
Niacin is essential for the synthesis of various hormones including sex hormones, cortisone, thyroxin and insulin. Nicotinic acid is part of the glucose tolerance factor, a compound which enhances the body’s response to insulin (the hormone responsible for transporting glucose into cells and storing it in the liver and muscles).
Niacin is essential for the normal functioning of the brain and nervous system. It is used in treating schizophrenia and other mental illnesses, and a memory-enhancer.
Nicotinic acid (but not nicotinamide) given in drug dosage improves the blood cholesterol profile, and has been used to clear the body of organic poisons, such as certain insecticides.
The repair of the genetic damage that occurs when cells are exposed to viruses, drugs or other toxic substances requires niacin-dependent coenzymes.
8.15 .8 DEFICIENCY
The disease is associated with poor socio-economic group especially in the middle-aged population, whose diet consists of cereals which contain incomplete protein for eg. Maize.
Sorgum, Corn. Diets poor in proteins with high levels of leucine eg. Sorgum and Corn resulted in niacin deficiency due to amino acid imbalance as reported by Gopalan and Srikantia from Andhra Pradesh, India. Recent studies have documented that leucine inhibits tryptophan uptake resulting in diminished supply of precursors for nicotinamide synthesis.
The deficiency of niacin which causes pellagra involves gastro intestinal tract, the skin and the nervous system. Non-specific signs such as anorexia, nausea, digestive disturbances and emotional changes like anxiety, irritability, insomnia etc may be seen in the early stages.
However symptoms of mild niacin deficiency include:
indigestion
fatigue
sores
vomiting
depression
loss of weight,
loss of appetite
Severe deficiency of niacin causes pellagra involves gastro intestinal tract, the skin and the nervous system.
Early signs include fatigue, loss of weight, loss of appetite and generally poor health.
Sore tongue, mouth, throat with glossitis extending throughout the gastro intestinal tract is present. This is because of the inflammation in the mucous membrane of the gastro intestinal tract. The inflammation can result in severe glossitis, stomatitis, oesophagitis, gastritis and enteritis with bloody diarrhea. The tongue and also lips becomes extra
ordinary red in colour, the mouth becomes so sore that it becomes difficult to eat and swallow. Nausea and vomiting are followed by severe diarrhea.
A characteristic symmetrical dermatitis will be found on exposed surfaces of the body, hands, forearms, elbows, feet, legs, knees and neck appears as the skin is photosensitive.
In case of dermatitis skin becomes red, gets swollen, tender and resembles sun burn. The lesions are hyoerkeratotic and hyper pigmented followed by secondary infections in rare cases. The lesions on the neck appear in the form of a necklace called “casal’s necklace”.
If this condition is not treated skin becomes rough, cracked, scaly and ulcerated. The skin change is because of decreased collagen content and increased urocanic acid and alteration in copper metabolism.
Neurological symptoms include confusion, dizziness, poor memory and irritability leading to hallucinations and dementia gets severely increased. Insomnia being the characteristic feature of pellagra it can manifest in disorientation, hallucinations and delirium. The peripheral nerve may be affected decreased nerve conduction, improper coordination and tremors. Spastic paraplegia has also been reported.
Pellagra is also seen secondary to alcoholism and malabsorption. Studies have indicated that, in patients with alcoholic pellagra, niacin deficiency may be an important factor influencing both the onset and severity of this condition. Patients with alcoholism typically experience increased intestinal permeability, leading to negative health outcomes.
Drug-induced metabolic aberrations can also lead to pellagra. It may occur in carcinoid syndrome, patients with aminoaciduria- an autosomal genetic disorder, where there are defects in absorption of tryptophan in the intestines and the kidney. Hartnup disease is a hereditary nutritional disorder resulting in niacin deficiency. This condition was first identified in the 1950s by the Hartnup family in London. It is due to a deficit in the intestines and kidneys, making it difficult for the body to break down and absorb dietary tryptophan. The resulting condition is similar to pellagra, including symptoms of red, scaly rash, and sensitivity to sunlight.
To summarize the classic manifestations of pellagra are
Dermatitis
Diarrhea
Dementia and finally
Death
Remember the classic D’S for the final stages of pellagra 8.15 .9 LET US SUM UP
Niacin is a major B-complex vitamin that plays an important role in energy metabolism. It occurs mainly as the nicotinamide nucleotides i.e., NAD and NADP in animals. In in some foods, niacin may be bound covalently to complex carbohydrates and called niactin, or it may be bound to small peptides called nicainogens. This bound form is seen in corn, wheat and some other cereal products. NAD and NADP are absorbed in the stomach, but they are readily absorbed in the small intestine. The absorption is through a sodium-dependent system, however it is concentration dependent.NAD and NADP play an important role as coenzymes. Oxidative reactions in which NAD participates and is reduced to NADH include glycolysis, oxidative decarboxylation of pyruvate etc. NADPH is used in a variety of reductive biosynthesis including fatty acid synthesis, cholesterol and steroid hormone synthesis, regeneration of glutathione, vitamin c and thioredoxin. Classical deficiency of niacin results in a condition known as pellagra.
The four D’s- dermatitis, dementia, diarrhea and death- are often used to remember signs of pellagra.
