Nicotinic acid specificity

Pellagra-associated encephalopathy has been suspected as an adverse effect of isoniazid administration in several patients with tuberculosis. Deficiency of niacin (nicotinic acid) is characterized by dermatitis, diarrhea, and dementia. Other symptoms can occur, such as seizures, hallucinations, spasticity, and glossitis. Pellagra induced by isoniazid is promoted by malnutrition or a vegetarian diet with low intake of the nicotinamide precursors tryptophan and nicotinic acid. Specific supplementation is essential (10). 

Both nicotinic acid and nicotinamide have been assayed by chemical and biological methods. Owing to the fact that niacin is found in many different forms in nature, it is important to indicate the specific analyte in question. For example, if biological assay procedures are used, it is necessary to indicate whether the analysis is to determine the quantity of nicotinic acid or if niacin activity is the desired result of the analysis. If nicotinic acid is desired, then a method specific for nicotinic acid should be used. If quantitation of niacin activity is the desired outcome, then all compounds (bound and unbound) which behave like niacin will assay biologically for this substance (1). 

For more specific analysis, chromatographic methods have been developed. Using reverse-phase columns and uv detection, hplc methods have been appHed to the analysis of nicotinic acid and nicotinamide in biological fluids such as blood and urine and in foods such as coffee and meat. Derivatization techniques have also been employed to improve sensitivity (55). For example, the reaction of nicotinic amide with DCCI (AT-dicyclohexyl-0-methoxycoumarin-4-yl)methyl isourea to yield the fluorescent coumarin ester has been reported (56). After separation on a reversed-phase column, detection limits of 10 pmol for nicotinic acid have been reported (57). 

Bakers inactive dry yeast is also widely used in the food industry. This yeast may be grown specifically as a food supplement and consequently there is a choice in its composition by varying growth conditions and feedstock makeup. It can possibly produce high levels of nicotinic acid and thiamin, the cmde protein content can be raised to 50—55% and it can be used as a vehicle for the incorporation of micronutrients such as selenium or chromium into the diet. 

A limited number of pure substances are available from NIST, primarily clini-cally-relevant compounds such as cholesterol, urea, uric acid, creatinine, glucose, cortisol, tripalmitin, and bilirubin (NIST SRM website). These compounds are certified for purity (greater than 99 %) and are used as primary calibrants in definitive methods for these clinical analytes (see below). Several additional pure substances are available for specific applications such as microchemistry, i.e. elemental composition (acetanilide, anisic acid, cystine nicotinic acid, o-bromobenzoic acid, p-fluoro-benzoic acid, m-chlorobenzoic acid), polarimetric standards (sucrose and dextrose), acidimetric standard (benzoic acid and boric acid). Only three pure substance NIST RMs are available for environmental contaminants, namely the chlorinated pesticides, lindane, 4,4 -DDT, and 4,4 -DDE. 

Specific concomitant medications or consumptions (check specific statin package insert for warnings) fibrates (especially gemfibrozil, but other fibrates too), nicotinic acid (rarely), cyclosporine, azole antifungals such as itraconazole and ketoconazole, macrolide antibiotics such as erythromycin and clarithromycin, protease inhibitors used to treat Acquired Immune Deficiency Syndrome, nefazodone (antidepressant), verapamil, amiodarone, large quantities of grapefruit juice (usually more than 1 quart per day), and alcohol abuse (independently predisposes to myopathy)... 

Recently, Prasad et al. cloned a mammalian Na+-dependent multivitamin transporter (SMVT) from rat placenta [305], This transporter is very highly expressed in intestine and transports pantothenate, biotin, and lipoate [305, 306]. Additionally, it has been suggested that there are other specific transport systems for more water-soluble vitamins. Takanaga et al. [307] demonstrated that nicotinic acid is absorbed by two independent active transport mechanisms from small intestine one is a proton cotransporter and the other an anion antiporter. These nicotinic acid related transporters are capable of taking up monocarboxylic acid-like drugs such as valproic acid, salicylic acid, and penicillins [5], Also, more water-soluble transporters were discovered as Huang and Swann [308] reported the possible occurrence of high-affinity riboflavin transporter(s) on the microvillous membrane. 

Yusufi ANK, Cheng J, Thompson MA, Chini EN, Grande JP 2001 Nicotinic acid-adenine dinucleotide phosphate (NAADP) elicits specific microsomal Ca2+ release from mammalian cells. Biochem J 353 531—536... 

Recently nicotinic acid has been found to lower serum cholesterol in hypercholesteremia, and also in normal persons and rabbits (A3, F2). It was shown that the hypercholesteremia, induced by a 48-hour fast, could be completely corrected by giving the animals large doses of nicotinic acid during the fast. In contrast to nicotinic acid, nicotinamide does not lower the cholesterol level (M10). Several explanations are offered for the action of nicotinic acid (1) it inhibits cholesterol biosynthesis, (2) it interferes with coenzyme A, and (3) it involves a hitherto unknown pharmacologic effect. The renewed clinical interest in nicotinic acid induced us to look for a more specific and sensitive assay for nicotinic acid (B7, M8). 

The first biochemical analysis of a selenium-containing XDH was reported in 1999 by Andreesen s group. This preparation was specific for xanthine and did not hydroxylate nicotinic acid. Moreover, the enzyme contained FAD, acid-labile sulfur, iron, and a dinucleotide molybdenum cofactor. Most intriguing was the near-equimolar presence of tungsten and molybdenum. It should be noted that the culture medium contained nearly equimolar levels of these metals, making one wonder whether the specificity of this enzyme for metal may be relaxed (i.e., can use Mo or W). Selenium was also found in the preparation and could be released by treatment with cyanide indicating it was also a labile cofactor. This further confirmed the chemical nature of the cofactor from the NAH enzyme from the same strain. ... 

The laboratory must be informed when the therapeutic regimens include drugs specifically administered to change the blood level of a biochemical constituent. Cholestyramine resin, a nonabsorbable anion exchange resin administered orally to patients with hyperlipoproteinemia produced a 24% decline in serum cholesterol levels in 14 patients with essential hypercholesterolemia. In these patients the mean cholesterol fell from 414 98 mg/100 ml to 176 21 mg/100 ml (FI). Pectin added to the diet caused a 5% decrease in serum cholesterol values (K4), as did an oral hydrophobic colloid (G4). Levels fell in one case from 220 mg/ 100 ml to 160 mg/100 ml (G4). Nicotinic acid, neomycin, and p-chloro-phenoxyisobutyrate have all been used to reduce serum cholesterol (G7). 

In the form in which they are consumed, many vitamins are not biologically active. For several water-soluble vitamins such as thiamine, riboflavin, nicotinic acid, pyridoxine, activation includes phosphorylation or, as is the case with riboflavin and nicotinic acid, coupling to purine or pyridine nucleotides is required. In their major known actions, water-soluble vitamins participate as cofactors for specific enzymes, whereas at least two fat-soluble... 

On the other hand, in recent years there has been an increasing role for the use of certain vitamins in the prevention and management of specific diseases. The use of nicotinic acid in hyperlipidemia is an old but still a good example for such use. 

Substituted nicotinic acid derivatives are useful in the synthesis of pesticides and pharmaceuticals as specific inhibitors of NAD and/or NADP dependent enzymes. 6-Hydroxynicotinic acid is a very useful intermediate in the synthesis of such inhibitors. 

Labeling by deuterium or carbon-13 always leads to unequivocal signal identification of specific carbon atoms [600, 602, 640], After the administration of [5,6-14C-13C2]nicotinic acid to Nicotiana tabacum and N. glauca labeled anabasine anatabine, nicotine and nomicotine could be isolated. The satellites at the resonances of the labeled natural products helped to complete the signal assignments of the 13C NMR spectra of these alkaloids [602]. 

The degradation of nicotinic acid by Clostridium barkeri involves the cleavage of the intermediate 2,3-dimethylmalate 132 from which propionic and pyruvic acids are formed by a specific lyase (EC 4.1.3.32). In the reverse direction, the enzyme must have the unusual capacity to deprotonate propionic acid at the a-carbon instead of the carboxylic acid function, or next to an anionic car-boxylate. Purified dimethylmalic acid aldolase has been used to catalyze the stereospecific addition of 133 to the oxoacid acceptor, yielding the (2R,3S) configurated dimethylmalic acid 132 at the multi-gram scale [381]. The substrate tolerance of this enzyme has not yet been determined. 

Similarly, DuPont employs a nitrile hydratase (as whole cells of P. chlororaphis B23) to convert adiponitrile to 5-cyanovaleramide, a herbicide intermediate [122]. In the Lonza nitrotinamide (vitamin B6) process [123] the final step (Fig. 1.42) involves the nitrile hydratase (whole cells of Rh. rhodocrous) catalysed hydration of 3-cyanopyridine. Here again the very high product purity is a major advantage as conventional chemical hydrolysis affords a product contaminated with nicotinic acid, which requires expensive purification to meet the specifications of this vitamin. 

After it had been established that pellagra was a nutritional deficiency disease, the next problem was to discover the missing nutrient. Additional dietary protein was shown to be beneficial, thus it was concluded that pellagra was because of a protein deficiency. This view, and later that it was more specifically from a deficiency of tryptophan, was held for some time. In 1938, Spies and coworkers showed that nicotinic acid would cure pellagra thereafter it was gradually accepted that it was a niacin deficiency disease. 

There is confusion in the literature because of the North American usage of the name niacin to mean specifically nicotinic acid, whereas the amide is known as niacinamide. The name niacin was coined in the late 1940s when the role of deficiency in the etiology of pellagra was realized, and it was decided that dietary staples should be fortified with the vitamin. It was felt that nicotinic acid was not a suitable name for a substance that was to be added to foods, both because of its phonetic (and chemical) relationship to nicotine and because it is an acid. 

Methylation is a common feature of the metabolism of phenols and A-heterocyclic compounds. Thus, phenolic steroids, adrenaline, and some other catecholamines undergo O-methylation, while pyridine, nicotinic acid, and normorphine undergo N-methylation. The reaction occurs under the influence of 5-adenosylmethionine and a non-specific methyl transf erase. 

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