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PubMed2002

A molybdenum-containing dehydrogenase catalyzing an unusual 2-hydroxylation of nicotinic acid.

An enzyme of Ralstonia/ Burkholderia strain DSM 6920 catalyzing the initial hydroxylation of 6-methylnicotinic acid at position 2 was purified to apparent homogeneity. It also catalyzed the unusual conversion of nicotinic acid to 2-hydroxynicotinic acid and was therefore designated as nicotinic acid dehydrogenase (NDH). Native NDH had a molecular mass of 280 kDa and was composed of subunits of 75, 30 and 16 kDa. It contained molybdenum, iron, acid-labile sulfur and FAD in a ratio of 1.6:7.3:8.0:0.6 mol(-1) of native enzyme. The molybdenum cofactor was characterized as molybdopterin cytosine dinucleotide. Zinc was identified as an additional metal ion in a molar ratio of 1.8 mol mol(-1) of native enzyme. Purified NDH exhibited a maximal specific activity of 22.6 micromol nitro blue tetrazoliumchloride reduced min(-1) mg(-1) of protein, using nicotinic acid as electron donor. The apparent K(m) value for nicotinic acid was determined to be 154 microM. Pyridine-3,5-dicarboxylic acid and quinoline-3-carboxylic acid were further substrates, but exhibited significantly different activity pH optima. Several artificial electron acceptors were reduced by NDH, but no activity was detected with NAD or O(2). NDH was inactivated upon incubation with cyanide, but no loss of activity was obtained in the presence of arsenite.

Hydroxylation↗
PubMed1988

Studies on intestinal lymphatic absorption of drugs. II. Glyceride prodrugs for improving lymphatic absorption of naproxen and nicotinic acid.

A series of alpha- and beta-monoglycerides and triglyceride derivatives of naproxen or nicotinic acid were synthesized and investigated in order to elucidate the molecular form of the derivative with properties that enhanced lymphatic absorption. The lymphatic absorption rate was increased by adjusting the length of an n-alkyl chain introduced between the alpha- or beta-position of glycerol and the drug residue. The alpha- and beta-monoglyceride derivatives (containing an n-alkyl chain) were approximately equal in lymphatic absorption rates, but differed markedly in the concentration of the di- and triglyceride analogues in the lymph lipids. The lymphatic absorption of triglyceride derivatives, drugs combined directly with beta-position of glycerol, was low in comparison with the monoglyceride derivatives. Compared with nicotinic acid, the alpha-monoglyceride derivative (n-alkyl chain length, Cn = 20) of nicotinic acid provided a higher AUC0-8 h value of free nicotinic acid and maintained a lower level of free fatty acids in blood.

Animals↗
PubMed1975

[Nicotinic acid blood levels after application of xanthinolnicotinate in a new galenic retard preparation].

Nicotinic acid blood level determinations were carried out in 30 male test subjects following application of xantinol-nicotinate in a new galenic retard preparation. The investigations showed that there is a continuous absorption of the agent--lasting for a longer period--with a maximum of blood level values between the 5th and 7th hour. In comparative studies with non-retarded xantinol-nicotinate the peak of concentration is already reached 1 h after application. The use of pharmacokinetic methods showed that by the retardation of xantinol-nicotinate there are no losses of absorption of nicotinic acid--as compared with the non-retarded forms. By the special galenic properties of the new retard form therapeutically effective nicotinic acid blood levels lasting for more than 8 h with an ascertained biological availability are attained.

Adenosine Triphosphate↗
PubMed1986

Intestinal uptake of nicotinic acid as a function of microclimate-pH.

The investigations aimed at clarifying the pH-dependence of 3H-nicotinic acid uptake into isolated strips of rat jejunum. Nicotinic acid is a weak-electrolyte with pKa 4.90. Thus, it was anticipated that the penetration rate of this vitamin into the intestinal epithelial cells is closely related to the amount of the diffusible i.e. non-ionic form which for its part is a function of the "virtual pH" on the mucosal surface. As determined by microelectrodes the surface pH was found to be between 5.41 and 6.80 when the strips were incubated in buffers between pH 4.5 and 9.0. At surface pH 5.83 the unidirectional flux rate was twice as high, at pH 5.41 three times as high as at surface pH values between 5.95 and 6.80. At each pH the unidirectional flux of nicotinic acid was linearly dependent on the substrate concentration in a range between 0.1 microM and 1 mM, indicating simple diffusion as transport mechanism. Accordingly, the uptake rate was not affected by the substrate analogon, isonicotinic acid (5 microM and 250 microM). It can be concluded that the predominant part of the nicotinic acid is transported through the brush border membrane obeying the laws of a non-ionic diffusion. A relatively small portion of this substrate, however, was taken up by the tissue even when the vitamin was entirely dissociated, possibly by ionic diffusion or by binding.

Animals↗
PubMed1984

Induction of peroxisomal enzymes and palmitoyl-CoA hydrolase in rats treated with cholestyramine and nicotinic acid.

Male Wistar rats were given 200 mg/kg/day nicotinic acid or 1000 mg/kg/day cholestyramine by stomach tube for ten days. Peroxisomal palmitoyl-CoA oxidation (cyanide-insensitive) and the activities of palmitoyl-CoA hydrolase and urate oxidase were significantly increased in the total liver homogenate. Subcellular fractionation showed enhanced enzyme activities after drug treatment mainly in the peroxisome-containing fractions. The increase in urate oxidase activity and its subcellular distribution suggest that the tested drugs induce core-containing peroxisomes. The findings are similar to those previously reported with low doses of peroxisome-proliferating hypolipidemic drugs and with acetylsalicylic acid, a drug which is structurally similar to nicotinic acid. Since cholestyramine is not absorbed, its influence on hepatic enzymes probably occurs indirectly as a consequence of enhanced catabolism of cholesterol.

Animals↗
PubMed1996

Properties of the selenium- and molybdenum-containing nicotinic acid hydroxylase from Clostridium barkeri.

NADP(+)-coupled nicotinic acid hydroxylase (NAH) has been purified to near-homogeneity from Clostridium barkeri by an improved purification scheme that allowed the isolation of milligram amounts of enzyme of higher specific activity then previously reported. NAH is most stable at alkaline pH in the presence of glycerol. The protein which consists of four dissimilar subunits occurs in forms of different molecular masses. There are 5-7 Fe, 1 FAD, and 1 Mo per 160 kDa protein promoter. Mo in the enzyme is bound to a dinucleotide form of molybdopterin and is coordinated with selenium. Mo(V), flavin radical, and two Fe2S2 clusters could be observed with EPR spectroscopy. The Se cofactor which is essential for nicotinic acid hydroxylase activity could be released from NAH as a reactive low molecular weight compound by a number of denaturing procedures. Parallel losses of Se and catalytic activity were observed during purification and storage of the enzyme. Addition of sodium selenide or selenophosphate did not restore the catalytic activity of the enzyme. Instead, NAH is reversibly inactivated by these compounds and also by sulfide. Cyanide, a common inhibitor of Mo-containing hydroxylases, does not affect NAH catalytic activity. The "as isolated" enzyme exhibits a Mo(V) EPR signal (2.067 signal) that was detected at early stages of purification. NAH exhibits a high substrate specificity toward electron donor substrates. The ability of a nicotinate analog to reduce NAH (disappearance of 2.067 signal) correlates with the rate of oxidation of the analog in the standard assay mixture. The properties of NAH differentiate the enzyme from known Mo-containing hydroxylases.

Amino Acid Sequence↗
PubMed1993

Simultaneous determination of nicotinic acid and its two metabolites in human plasma using solid-phase extraction in combination with high performance liquid chromatography.

A high performance liquid chromatographic method for the simultaneous quantitative determination of nicotinic acid, nicotinamide and nicotinuric acid in human plasma is described. The method is based on solid phase extraction in combination with ion-paired reversed phase high performance liquid chromatography. Recoveries of nicotinic acid, nicotinamide and nicotinuric acid are 92.9, 95.8 and 87.8%, respectively. The procedure shown was applied to the determination of the plasma time-concentration profile of nicotinic acid, nicotinamide and nictotinuric acid after nicotinic acid ingestion in humans.

Adult↗
PubMed1999

Decreased hemolysis and lipid peroxidation in blood during storage in the presence of nicotinic acid.

BACKGROUND AND OBJECTIVES: There is increase in lipid peroxidation with consequent increase in hemolysis when blood is stored in di-(2-ethyl hexyl)phthalate (DEHP) plasticized bags. Studies carried out by us and others have indicated the ability of red cells to synthesize NAD+ from added nicotinic acid. Apart from the role of NAD+ in glycolysis, NADPH is required for reduction of oxidized glutathione to its reduced form by glutathione reductase. Reduced glutathione is an important antioxidant, which protects cell membrane from oxidative damage. Reduced glutathione is also involved in the regeneration of vitamin E, another important membrane antioxidant. In view of these, a study was undertaken to find out the effect of addition of nicotinic acid to the citrate-phosphate-dextrose-adenine (CPDA) solution on lipid peroxidation and integrity of red cells when whole blood is stored in DEHP plasticized bags. MATERIALS AND METHODS: Blood was collected in Penpol blood storage bags (which is a DEHP plasticized bag) in CPDA solution in the presence and absence of nicotinic acid. Various parameters of lipid peroxidation and membrane stability - level of malondialdehyde (MDA), conjugated dienes, vitamin E, reduced glutathione, plasma Hb and K+, levels of adenosine triphosphate (ATP) and 2,3-diphosphoglycerate (2,3-DPG) were studied in the blood samples after various periods. RESULTS: Plasma Hb and K+ concentrations were significantly lower in the presence of added nicotinic acid both after 28 and 42 days. Concentration of MDA and conjugated dienes was lower and the levels of reduced glutathione and vitamin E higher in the presence of nicotinic acid. ATP levels were not significantly different, but 2,3-DPG levels were higher. pH of the blood was nearer to 7.0 in the presence of nicotinic acid, while leaching out of DEHP into the blood was significantly lower. CONCLUSION: Inclusion of nicotinic acid in the CPDA solution has a beneficial effect in that (1) it reduces plasma Hb and K+; (2) reduces lipid peroxidation and increases antioxidant protection; (3) maintains pH nearer to 7.0, and (4) decreases the leaching out of DEHP into the blood.

2,3-Diphosphoglycerate↗
PubMed1998

Synthesis of NAD+ in erythrocytes incubated with nicotinic acid and the effect of di-(2-ethyl hexyl) phthalate (DEHP).

Synthesis of NAD+ from nicotinic acid by erythrocytes incubated in SAGM phosphate solution and effect of di-[2-ethyl hexyl] phthalate, a plasticizer commonly used in PVC blood/component storage bags, on this synthesis was studied. Erythrocytes are able to synthesise NAD+ in SAGM (sodium chloride, adenine, glucose, mannitol) phosphate solution and this synthesis was more in the presence of added nicotinic acid (optimum concentration 1 mM). The level of NAD+ decreased when the incubation period was increased from 24 to 48 hr. Glutamine had a deleterious effect on this synthesis, possibly due to the decrease in pH. Di-[2-ethyl hexyl] phthalate had an inhibitory effect on NAD+ synthesis when the cells were incubated in SAGM phosphate solution, either alone or in the presence of added nicotinic acid. There was significant decrease in the release of potassium and haemoglobin from the cells in the presence of nicotinic acid, indicating increased red cell stability.

Adenine↗
PubMedDate not supplied

[Effect of nicotinic acid and prozerin on choline metabolism].

The content and specific activity of labelled methyl groups of choline and phosphorylcholine in the brain, liver and skeletal muscles of rats was studied as affected by nicotinic acid and prozerin, injected subcutaneously 4h before decapitation. It was found that under the effect of prozerin the specific activity of choline lowers only in the muscles and nicotinic acid evokes its decrease in the liver and muscles. The specific activity of phosphorylcholine lowers in the brain and liver with introduction of prozerin and nicotinic acid. The intensity of phosphorylcholine phosphate renewal increases in the liver and skeletal muscles after introduction of both prozerin and nicotinic acid. The activity of choline dehydrogenase in the liver homogenates lowers only with injection of nicotinic acid.

Animals↗
PubMed2002

Concurrent quantification of quinolinic, picolinic, and nicotinic acids using electron-capture negative-ion gas chromatography-mass spectrometry.

Quinolinic, picolinic, and nicotinic acids and nicotinamide are end products of the kynurenine pathway from l-tryptophan and are intermediates in the biosynthesis of nicotinamide adenine dinucleotide. These compounds are involved in complex interrelationships with inflammatory and apoptotic responses associated with neuronal cell damage and death in the central nervous system. To facilitate the study of these compounds, we have utilized gas chromatography-mass spectrometry in electron capture negative ionization mode for their concurrent trace quantification in a single sample. Deuterium-labeled quinolinic, picolinic, and nicotinic acids were used as internal standards and the compounds were converted to their hexafluoroisopropyl esters prior to chromatography. Nicotinamide was readily quantified after conversion to nicotinic acid using gas-phase hydrolysis-a process which did not affect the deuterated internal standards. The on-column limit of quantification was less than 1 fmol for each of the analytes and calibration curves were linear. A packed column liner was used in the gas chromatograph inlet to effectively eliminate sample interference effects in the analysis of trace (femtomolar) levels of quinolinic acid. The method enables rapid and specific concurrent quantification of quinolinic, picolinic, and nicotinic acids in tissue extracts and physiological and culture media.

Animals↗
PubMed1997

The effects of glyceryl trinitrate and nicotinic acid ointments during cold exposure.

The aim of the present experimental study was to examine the effects of local application of glyceryl trinitrate and nicotinic acid on the cold-provoked haemodynamic responses, pain and hand dexterity. Ten young healthy volunteers participated in this randomized, cross-over study with three phases at least two days apart. Five cm of 2% glyceryl trinitrate ointment, 10% nicotinic acid ointment or placebo ointment was applied on the back of each subject's both hands 15 min. before the 7 min. cold exposure. Blood pressure and heart rate were measured prior to, during and after the cold exposure. In addition, the effect of cold on hand dexterity was evaluated by the Purdue pegboard test and the subjects assessed the pain in their hands during the cold exposure. Pretreatment with glyceryl trinitrate ointment counteracted the cold-induced haemodynamic response, as evidenced by a significantly (P < 0.05) smaller mean increase in the systolic blood pressure from the baseline compared with placebo. In contrast, the cold-induced increase in the systolic blood pressure observed after pretreatment with nicotinic acid ointment did not differ from placebo. Both glyceryl trinitrate and nicotinic acid alleviated the cold-induced pain, but neither of them prevented the deterioration of hand dexterity. In conclusion, the haemodynamic response provoked by a brief cold exposure could to some extent be counteracted by pretreatment with glyceryl trinitrate ointment, but not with nicotinic acid ointment, compared with placebo.

Administration, Topical↗
PubMed2003

Permeation, metabolism and site of action concentration of nicotinic acid derivatives in human skin. Correlation with topical pharmacological effect.

A novel methodology for establishing a pharmacological dose-effect relationship of methyl nicotinate, hexyl nicotinate and nicotinic acid acting as peripheral vasodilators in the skin following topical application is investigated. This methodology involves the estimation of the unbound drug concentration in the aqueous compartment at the site of action in tissue, termed C(*), which was evaluated as the pertinent concentration responsible for the pharmacological effect. Blood capillaries next to the epidermis-dermis boundary were postulated to be the relevant site of action. C(*) was estimated from drug transport parameters for different layers of human cadaver skin determined in vitro. Immunohistochemical studies showed that the plane of separation of skin achieved by heat treatment was between the basal cells of the epidermis and the lamina lucida, confirming the integrity of the epidermis and the dermis used in the experiments. The permeation rate for epidermis increased drastically with increasing lipophilicity of the drug. Dermis permeability was roughly the same for all three compounds. The epidermis represented the major transport barrier in vitro for methyl nicotinate and nicotinic acid but not for hexyl nicotinate. The esters were metabolised to nicotinic acid during tissue permeation to an extent that was rather limited for the epidermis but very pronounced for the dermis. Nonspecific alpha-naphthylacetate-esterase activity was predominantly located in the dermis, which was in agreement with the metabolism results. The drugs were applied each at three different concentrations in vivo to the ventral forearm of healthy human volunteers and vasodilation was evaluated based on skin erythema which was quantified by measuring colour change of reflected light. Area under the curve of the change of colour co-ordinates as a function of time was used as a measure of pharmacological effect. The pharmacological effect of all three drugs was comparable when similar C(*) values were considered, even though the concentrations applied to the skin differed by orders of magnitude. The effect showed a strong positive dependence on C(*). Methyl and hexyl nicotinate showed identical, nearly sigmoidal effect/C(*)-profiles, while the profile for nicotinic acid was linear, suggesting a possible difference in the intrinsic pharmacological potency between the esters and the acid. These results demonstrate the validity of C(*) as the relevant drug concentration for the cutaneous pharmacological effect of the topically applied drugs and underline the usefulness of the presented methodology for establishing dose-response relationships in dermal therapy and expressing bioavailability.

Administration, Topical↗
PubMed1985

Disposition of etofibrate, clofibric and nicotinic acid esters, and their products in dogs.

Etofibrate, the ethylene glycol diester of clofibric and nicotinic acids, on intravenous infusion into dogs, has a terminal half-life of 2 min. The intermediate half-esters, the nicotinate and the clofibrate, have respective terminal half-lives of 4.6 and 1.7 min and appear fleetingly when etofibrate is administered. In contrast to the 42-h terminal half-life of clofibric acid, the other final transformation product, nicotinic acid, shows saturable or dose-dependent pharmacokinetics in dogs that conform to the Michaelis-Menten equation with a terminal half-life of 4.4 min at low concentrations (less than 6.9 microM/kg). Three distinct metabolites of nicotinic acid can be identified and assayed chromatographically in the urine. The partition properties were similar to nicotinic acid. Nicotinic acid is excreted 30% unchanged into urine with a renal clearance of 70 mL/min in 27-kg dogs.

Animals↗
PubMed1979

Effects of nicotinic acid therapy on plasma high density lipoprotein subfraction distribution and composition and on apolipoprotein A metabolism.

This report describes the effects of pharmacologic doses (3 g/d) of nicotinic acid on the plasma distribution and chemical composition of the high density lipoprotein (HDL) subfractions HDL(2) and HDL(3) and examines the influence of the drug on the metabolism of the major HDL apoproteins, apolipoproteins A-I (ApoA-I) and A-II (Apo-II). The drug lowered plasma cholesterol (15%, P < 0.05) and triglyceride (27%, P < 0.01); the former effect a result of a fall in the amount of cholesterol associated with very low density lipoproteins (31%, P < 0.02) and low density lipoproteins (36%, P < 0.02). Conversely, it raised plasma HDL cholesterol (23%, P < 0.05) and increased (by 345%) the plasma HDL(2):HDL(3) ratio. The latter derived from an absolute increment (646%) in circulating HDL(2), coupled with a fall (47%) in HDL(3). This change was not associated with major alterations in the overall cholesterol (free and esterified), triglyceride, phospholipid, or protein content of the subfractions; however, it was accompanied by substantial changes in their protein composition. In particular, the molar ratio of ApoA-I:ApoA-II in HDL(3) declined from 2.7:1 to 2.1:1 during nicotinic acid treatment.Significant perturbations of ApoA-I and ApoA-II metabolism accompanied the drug-induced HDL subfraction redistribution. Specifically, the plasma concentration of ApoA-I rose by 7% (P < 0.05) because of a decrease in its fractional catabolic rate. Moreover, whereas before treatment 6 and 94% of the plasma ApoA-I circulated with HDL(2) and HDL(3), after commencement of nicotinic acid therapy this distribution became 49 and 51% in HDL(2) and HDL(3), respectively. ApoA-II was found mainly in HDL(3), both before and during nicotinic acid treatment. Administration of the drug caused a 14% reduction in its plasma concentration (P < 0.05), which derived principally from a fall (22%, P < 0.01) in its synthetic rate. These data suggest that the effects of nicotinic acid on the HDL subfraction distribution may be mediated via (a) net transfer of ApoA-I from HDL(3) to HDL(2) and (b) a reduction in ApoA-II synthesis. Our present understanding of the association between HDL and atherosclerosis indicates that such changes may have prophylactic value in the prevention of coronary artery disease.

Adult↗