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PubMed1993

Nicotinamide exerts different acute effects on microcirculatory function and tissue oxygenation in rat tumors.

PURPOSE: Nicotinamide has been reported to preferentially radiosensitize tumor tissue, supposedly through a reduction in tumor hypoxia. This may occur as a result of nicotinamide-induced changes in tumor blood flow and therefore the present study was undertaken to evaluate the effect of nicotinamide on circulatory parameters in skeletal muscle and tumor tissue (subcutaneously-implanted DS-sarcomas) of the rat. METHODS AND MATERIALS: Mean arterial blood pressure (measured in the common carotid artery using a pressure transducer) and red blood cell flux (as measured by laser Doppler flowmetry) were continuously monitored for 120 min following a single intraperitoneal application of nicotinamide (500 mg/kg). An arterial blood pressure/laser Doppler flux ratio was estimated for tumor and muscle tissue. RESULTS: Nicotinamide significantly reduced the mean arterial blood pressure to a minimum value 25% below the pretreatment value 20 min after the commencement of drug administration, with partial recovery thereafter. Red blood cell flux through tumor tissue, following an initial rapid decrease, rose steadily to values 34% above those measured in control animals at t = 60 min, while the arterial blood pressure/laser Doppler flux ratio in tumor tissue fell to values 34% below those of control animals. In skeletal muscle similar trends were seen although the changes were not of the same extent as those seen in tumor tissue. Tumor pO2 was measured 60 min following i.p. application of nicotinamide using polarographic needle electrodes. Despite the significant increase in blood flow following nicotinamide, no significant difference was seen between pO2 histograms obtained in tumors in nicotinamide-treated and control animals. CONCLUSION: These findings suggest that nicotinamide preferentially improves tumor microcirculatory function and effectuates a decrease in the arterial blood pressure/laser Doppler flux ratio within tumor tissue, effects which reach their maximum approximately 60 min following nicotinamide administration.

Animals↗
PubMed2004

Thermodynamics of alpha-lactalbumin-DL-alpha-dipalmitoylphosphatidylcholine interactions and effect of the antioxidant nicotinamide on these interactions.

Differential scanning calorimetry has been used to understand the thermodynamics of the interactions of dl-alpha-dipalmitoylphosphatidylcholine (DPPC) with alpha-lactalbumin and the effect of the antioxidant nicotinamide on these interactions. Nicotinamide decreases the thermal transition temperature of both the lipid and the protein at high concentrations. The thermal unfolding transitions of the protein were two state and calorimetrically reversible. There was no significant change in the shape and thermodynamic parameters accompanying the lipid endotherms, suggesting that nicotinamide did not penetrate the lipid bilayer. The thermal unfoldings of alpha-lactalbumin in the presence of DPPC as cosolute also adhered to two-state reversible mechanism. The changes in the thermodynamic parameters accompanying the thermal transitions were small, indicating no significant interaction of alpha-lactalbumin with DPPC. The changes in the thermodynamic parameters indicate that the lipid bilayer organization, as well as the partitioning of the extrinsic protein alpha-lactalbumin into the bilayer, is not affected in the entire studied concentration range of the lipid. It is observed that the presence of increasing concentration of nicotinamide (as high as 1.0 mol dm(-3)) in the lipid-protein mixture does not affect its partitioning into the lipid bilayer, although nicotinamide preferentially interacts with alpha-lactalbumin. The change in the effect of nicotinamide on lipid transition temperature in the mixture and literature report suggests that nicotinamide may be forming a hydrogen-bonded complex with the protein through its amide functionality. The surface tension data of aqueous nicotinamide in combination with the thermal denaturation results of protein in presence of nicotinamide confirmed that surface tension effect does not have any significant contribution to the effect of nicotinamide on protein.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed2006

Nicotinamide adenine dinucleotide staining immediately following radio frequency ablation of renal tumors-is a positive stain synonymous with ablative failure?

PURPOSE: Nicotinamide adenine dinucleotide diaphorase staining is arguably the standard for assessing tissue viability following radio frequency ablation, yet the accuracy of this test is questionable. Thus, it is imperative to examine the reliability of nicotinamide adenine dinucleotide to predict ablation success. To evaluate the observation that immediate nicotinamide adenine dinucleotide staining may not be clinically reliable, we compared results from immediate post-ablation biopsies of renal tumors to radiological and clinical followup. MATERIALS AND METHODS: Laparoscopic radio frequency ablation was performed in 9 patients and 10 tumors using a temperature modulated radio frequency system. Cold cup biopsies were taken immediately following ablation, and processed for nicotinamide adenine dinucleotide and hematoxylin and eosin staining. Patients were then followed using contrast enhanced computerized tomography at regular intervals. RESULTS: Median tumor size was 2.3 cm. Hematoxylin and eosin stain diagnosed 8 renal cell carcinomas and 2 angiomyolipomas. A quarter of the renal cell carcinomas and both angiomyolipomas stained positive for scattered nicotinamide adenine dinucleotide diaphorase activity immediately after RFA. Mean followup for the nicotinamide adenine dinucleotide positive tumors was 28.5 months (range 24 to 30) and for the nicotinamide adenine dinucleotide negative tumors was 25 months (range 18 to 30). There was no evidence of local tumor recurrence in any patient. CONCLUSIONS: Four lesions had nicotinamide adenine dinucleotide diaphorase activity on post-ablation biopsy suggesting retained viable tissue, yet there has been no recurrence during an average 2-year followup. While negative nicotinamide adenine dinucleotide staining is consistent with nonviability, these results suggest that false-positive staining can occur immediately following RFA, making the predictive value of positive nicotinamide adenine dinucleotide diaphorase staining unclear.

Adult↗
PubMed2002

Nicotinamide therapy protects against both necrosis and apoptosis in a stroke model.

BACKGROUND AND PURPOSE: Nicotinamide protects against brain damage in ischemia-reperfusion. However, the dosage and time of treatment require clarification. It is also not clear if nicotinamide can protect against both necrosis and apoptosis. METHODS: Dose-response and time-effect studies were designed. Transient focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) for 90 min. Different doses of nicotinamide were injected upon reperfusion. In time-effect studies, 500 mg/kg nicotinamide was administered at different times after the onset of reperfusion. Neurological finding scores were recorded. Infarct volumes were measured. RESULTS: In contrast to controls, neurological deficit scores and infarct volumes were greatly reduced by treatment with nicotinamide. The ED(50) of nicotinamide was 239+/-79 mg/kg (P=.95). It was found that nicotinamide injected during the first 6 h of reperfusion could effectively inhibit the development of brain damage. The optimal dose of nicotinamide was 500 mg/kg and gave a maximal response. CONCLUSIONS: Poly(ADP-ribose) polymerase (PARP) plays a key role in DNA repair in stroke. Excessive PARP activity consumes NAD leading to energy depletion and neuronal damage. As an inhibitor of PARP, nicotinamide promotes the supply of energy. The results suggest that early application of nicotinamide at a suitable dosage significantly ameliorates necrotic and apoptotic brain injury after focal ischemia-reperfusion.

Animals↗
PubMed2003

Ischemic preconditioning and nicotinamide in spinal cord protection in an experimental model of transient aortic occlusion.

OBJECTIVES: Spinal cord injury is a devastating complication after aortic surgery. The aim of the present study is to examine the effects of ischemic preconditioning (IPC) and nicotinamide containing perfusate in transient aortic occlusion in the rat. METHODS: Thirty-two male Spraque-Dawley rats under general anesthesia were randomly assigned to four groups (n=8 in each group). The infrarenal aortas were clamped for 45 min. Groups were as follows: Group 1, undergoing occlusion but receiving no treatment. Group 2, had 5 min of IPC before occlusion. Group 3, received nicotinamide (0.2 ml/l) during the transient occlusion. Group 4, received combined IPC (5 min) and nicotinamide infusion during the transient occlusion. The rats were then allowed for recovery and were tested for their neurological status. All animals were sacrificed at the end of the 48 h and spinal cords also examined histologically. Anti- poly (ADP-ribose) polymerase p85 fragment pAb was used as an immunohistochemical marker for detection of apoptosis. RESULTS: In 24 h paraplegia represented as grade 0 and 1 occurred in six animals in Group 1 and two animals in Groups 2 and 3 and one in Group 4. In 48 h six animals in Group 1 and only one animal in Groups 2 and 3 showed a paraplegia. The incidence of neurologic deficit was significantly reduced in animals who had IPC and nicotinamide infusion (P<0.05). At 48 h, combined IPC and nicotinamide showed a significant benefit compared to nicotinamide but not to the IPC alone. Histologic examination of the spinal cords revealed that a neuronal necrosis contributes to acute spinal cord degeneration after a period of aortic occlusion and both nicotinamide and IPC have protective effects against neuronal necrosis. No difference was found among the groups. CONCLUSIONS: Both IPC and nicotinamide are beneficial in protection against neurological damage in transient aortic occlusion. IPC alone as expected is significantly beneficial both at 24 and 48 h compared to controls. At 24 h combined nicotinamide and IPC show significant benefit compared to only nicotinamide, but this difference is not maintained at 48 h.

Animals↗
PubMed2002

Nicotinamide is not a substrate of the facilitative hexose transporter GLUT1.

It has been proposed that GLUT1, a membrane protein that transports hexoses and the oxidized form of vitamin C, dehydroascorbic acid, is also a transporter of nicotinamide (Sofue, M., Yoshimura, Y., Nishida, M., and Kawada, J. (1992) Biochem. J. 288, 669-674). To ascertain this, we studied the transport of 2-deoxy-D-glucose, 3-O-methyl-D-glucose, and nicotinamide in human erythrocytes and right-side-out and inside-out erythrocyte membrane vesicles. The transport of nicotinamide was saturable, with a K(M) for influx and efflux of 6.1 and 6.2 mM, respectively. We found that transport of the hexoses was not competed by nicotinamide in both the erythrocytes and the erythrocyte vesicles. Likewise, the transport of nicotinamide was not affected by hexoses or by inhibitors of glucose transport such as cytochalasin B, genistein, and myricetin. On the other hand, nicotinamide blocked the binding of cytochalasin B to human erythrocyte membranes but did so in a noncompetitive manner. Using GLUT1-transfected CHO cells, we demonstrated that increased expression of GLUT1 was paralleled by a corresponding increase in hexose transport but that there were no changes in nicotinamide transport. Moreover, nicotinamide failed to affect the transport of hexoses in both control and GLUT1-transfected CHO cells. Therefore, our results indicates that GLUT1 does not transport nicotinamide, and we propose instead the existence of other systems for the translocation of nicotinamide across cell membranes.

3-O-Methylglucose↗
PubMed1992

Possible multifunction of glucose transporter. Transport of nicotinamide by reconstituted liposomes.

A kinetic study of the uptake of nicotinamide by reconstituted liposomes containing the human erythrocyte glucose transporter, compared with that of D-glucose, demonstrated that the Km and Vmax. values were almost the same for each compound, and that the uptake of D-glucose was competitively inhibited by nicotinamide. At 20 mM concentration, 2-deoxy-D-glucose, 3-O-methyl-D-glucose and 4,6-O-ethylidene-D-glucose all caused 50% inhibition of nicotinamide uptake, but L-glucose and nicotinic acid were not inhibitory. Similar results were obtained for the uptake of D-glucose. Cytochalasin B binding to the liposomes was inhibited in a dose-dependent manner by either nicotinamide or D-glucose. Antibody for glucose transporter detected in band 4.5 by SDS/PAGE inhibited the uptake of D-glucose and nicotinamide. A possible uptake of nicotinamide by nucleoside transporter was excluded. In human erythrocytes, cytochalasin B binding was inhibited dose-dependently by either nicotinamide or D-glucose, and cytochalasin B depressed the uptake of both nicotinamide and 2-deoxy-D-glucose. These findings were well reproduced in the reconstituted liposomes. The very close similarities between uptake of nicotinamide and D-glucose suggest that the glucose transporter plays a direct role in transport of nicotinamide, which is structurally quite different from monosaccharides, and thus that the transporter is probably multifunctional.

Biological Transport↗
PubMed1990

Regulation of nicotinamide-adenine dinucleotide synthesis in erythrocytes of patients with hypoxanthine-guanine phosphoribosyltransferase deficiency and a patient with phosphoribosylpyrophosphate synthetase superactivity.

1. The synthesis of nicotinamide-adenine dinucleotide from nicotinamide and nicotinic acid was compared over different time scales at both physiological (0.7 mumol/l) and high (0.2-3 mmol/l) substrate concentrations in erythrocytes from three patients with hypoxanthine-guanine phosphoribosyltransferase (hypoxanthine phosphoribosyltransferase, EC 2.4.2.8) deficiency (including one Lesch-Nyhan patient) and from one patient with phosphoribosylpyrophosphate synthetase superactivity. The above disorders are associated with grossly altered erythrocyte nicotinamide-adenine dinucleotide levels. 2. At the physiological substrate concentration and incubation times up to 2 h, nicotinamide proved the most efficient nicotinamide-adenine dinucleotide precursor for erythrocytes from both patients and control subjects. The conversion of nicotinamide to its mononucleotide, but not further metabolism, was impaired in phosphoribosylpyrophosphate synthetase-mutant cells. The Lesch-Nyhan and phosphoribosylpyrophosphate synthetase-mutant cells were unusual in that both showed no further stimulation of nucleotide synthesis at 18 mmol/l Pi compared with 1 mmol/l. 3. At the high substrate concentrations, using 18 mmol/l Pi, nicotinamide was a poor precursor in all instances. Using nicotinic acid, nucleotide formation was 30-fold that from nicotinamide, reaching its maximum at 0.2 mmol/l. Conversion of nicotinic acid to nicotinamide-adenine dinucleotide in the phosphoribosylpyrophosphate synthetase-mutant cells was again grossly impaired. 4. There was no evidence for increased nicotinamide-adenine dinucleotide breakdown in the phosphoribosylpyrophosphate synthetase-mutant cells under any of the above conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Nicotinamide megadosing increases hepatic poly(ADP-ribose) levels in choline-deficient rats.

Previous work in our laboratory has shown that dietary megadoses of nicotinamide, used in the prevention of diabetes, cause increases in hepatic poly(ADP-ribose). Poly(ADP-ribose) is synthesized from NAD+ by a nuclear enzyme, poly(ADP-ribose)polymerase, which is activated by DNA strand breaks. The nicotinamide-induced increase in poly(ADP-ribose) could result from an increase in substrate, NAD+, or the induction of strand breaks in DNA. Strand breaks may result from the depletion of single carbon groups, through the excretion of methylated derivatives of nicotinamide. To differentiate between these mechanisms, a 3 x 3 factorial experiment was conducted in which rats were fed diets containing various supplements of choline bitartrate (0, 2, 20 g/kg diet) and nicotinamide (0, 1, 2 g/kg diet). At the conclusion of treatments, blood NAD+ and liver lipid, NAD+ and poly(ADP-ribose) levels were determined. Choline deficiency caused the characteristic accumulation of fat in the liver at all levels of nicotinamide. In choline deficient rats, nicotinamide supplements further increased liver lipid concentration. Blood and liver NAD+ concentrations were increased by nicotinamide supplementation, irrespective of choline status. In contrast, liver poly(ADP-ribose) levels were increased by nicotinamide supplementation only in choline deficient rats. These results show that nicotinamide-induced increases in poly(ADP-ribose) levels appear to be dependent on decreased methyl donor status and suggest that adequate choline status is important for preventing some deleterious effects of nicotinamide treatment.

Animal Nutritional Physiological Phenomena↗
PubMed1988

Nicotinamide as a rapid-acting inhibitor of renal brush-border phosphate transport.

Administration of nicotinamide to rats produces specific dose-dependent inhibition of Na+-dependent phosphate transport across the renal brush-border membrane (BBM) and an increase in urinary excretion of phosphate. The intracellular mechanism of action of nicotinamide is not well established. As a step in this direction, the present studies determined whether nicotinamide was a rapid- or slow-acting regulator of the BBM phosphate transport system. Nicotinamide (0.5 g/kg) inhibited Na+-dependent BBM phosphate transport under conditions when de novo protein synthesis was inhibited by cycloheximide (1.0 mg/kg). Furthermore, the degree of inhibition was not different from that achieved by nicotinamide alone, suggesting that the action of nicotinamide does not require de novo protein synthesis. Studies on the time course of the onset of nicotinamide action revealed inhibition of BBM phosphate transport within 1 h after injection of nicotinamide, even in rats pretreated with cycloheximide. The rapid response to nicotinamide and its independence of de novo protein synthesis characterize nicotinamide as a rapid-acting regulator of the Na+-dependent phosphate transport system in renal BBM.

Animals↗
PubMed1998

Mechanistic studies on hydrotropic solubilization of nifedipine in nicotinamide solution.

Nicotinamide is a hydrotropic agent that has been demonstrated to solubilize a wide variety of drugs through complexation. Past investigations on the potential interaction of nicotinamide with a solubilized drug have inadequately focused on aliphatic hydrotropes. This study examined the mechanism for the hydrotropic solubilization of nifedipine, a poorly water-soluble drug, in the aqueous solution of nicotinamide using not only nicotinamide analogues but also urea analogues as aliphatic hydrotropes. The values of stability constants, K1:2, at different temperatures in nicotinamide solution were determined by the phase solubility technique, and were utilized to estimate the thermodynamic parameters of complex formation between nifedipine and nicotinamide. The enthalpy change values suggested the participation of intermolecular forces other than hydrogen bonding in complexion. The aqueous solubility of nifedipine was measured in the presence of nicotinamide, urea and their analogues: N-methylnicotinamide, N,N-diethylnicotinamide, nipecotamide, methylurea, ethylurea and butylurea. The drug solubility increased in proportion to the amount of alkyl substituent on the amide nitrogen, and the solubilizing effect of butylurea was as high as that of nicotinamide. Furthermore, the relationship between the logarithmic drug solubilities in 1.0 M aqueous solutions of nicotinamide or urea analogues versus the logarithmic octanol-water partition coefficient values of ligands as an indication of hydrophobicity was found to be linear. The significant contributor to the hydrotropic solubilization of nifedipine with nicotinamide was therefore the ligand hydrophobicity rather than the aromaticity of the pyridine ring.

Drug Stability↗
PubMed1997

Nicotinamide reduces tumour interstitial fluid pressure in a dose- and time-dependent manner.

Nicotinamide radiosensitizes a number of experimental tumours, and increases blood flow and mean pO2 in some tumours. It has been suggested that nicotinamide reduces tumour interstitial fluid pressure (IFP), thereby reducing transient vessel non-perfusion and acute hypoxia, and radiosensitizing tumours. To test this hypothesis, tumour IFP, transient vessel non-perfusion, and radiosensitivity after nicotinamide administration were examined in the murine carcinoma NT. Nicotinamide at doses of 500 and 1000 mg kg-1 significantly reduced tumour IFP within 20 min of administration, with recovery to control values by 60-80 min; 100 mg kg-1 had no effect. The percentage of previously non-perfused vessels that became perfused 20 min after administering 1000 mg kg-1 of nicotinamide significantly exceeded the percentage that became perfused within 20 min in the absence of nicotinamide. By 90 min after nicotinamide administration, this differential effect was abolished. The correlation in the time courses of reduced IFP and increased vessel perfusion after nicotinamide administration suggest that decreased IFP may accompany vessel reperfusion. However, 1000 mg kg-1 of nicotinamide radiosensitized the NT carcinoma 80 min after administration, whilst no radiosensitization was seen within 10 min. Thus it is unlikely that increased vessel perfusion is the sole mechanism of nicotinamide-induced radiosensitization in this tumour.

Adenocarcinoma↗
PubMed2005

A two year observational study of nicotinamide and intensive insulin therapy in patients with recent onset type 1 diabetes mellitus.

BACKGROUND AND AIMS: A number of trials have evaluated residual beta-cell function in patients with recent onset type 1 diabetes mellitus (DM1) treated with nicotinamide in addition to intensive insulin therapy (IIT). In most studies, only a slight decline of C-peptide secretion was observed 12 months after diagnosis; however, no data is available on C-peptide secretion and metabolic control in patients continuing nicotinamide and IIT for up to 2 years after diagnosis. PATIENTS AND METHODS: We retrospectively analysed data from 25 patients (mean age 14.7 years +/- 5 SD) with DM1 in whom nicotinamide at a dose of 25 mg/kg b. wt. was added from diagnosis (< 4 weeks) to IIT (three injections of regular insulin at meals + one NPH at bed time) and continued for up to 2 years after diagnosis. Data were also analysed from patients (n = 27) in whom IIT was introduced at diagnosis and who were similarly followed for 2 years. Baseline C-peptide as well as insulin dose and HbA1c levels were evaluated at 12 and 24 months after diagnosis. RESULTS: In the course of the follow-up, patients on nicotinamide + IIT or IIT alone did not significantly differ in terms of C-peptide secretion (values at 24 months in the two groups were 0.19 +/- 0.24 nM vs 0.19 +/- 0.13 nM, respectively). Insulin requirement (0.6 +/- 0.3 U/kg/day vs 0.7 +/- 0.2 U/kg/day at 24 months, respectively) did not differ between the two groups. However, HbA1c was significantly lower 2 years after diagnosis in patients treated with nicotinamide + IIT (6.09 +/- 0.9% vs 6.98 +/- 0.9%, respectively, p < 0.01). No adverse effects were observed in patients receiving nicotinamide for 2 years. CONCLUSION: Implementation of IIT with the addition of nicotinamide at diagnosis continued for 2 years improves metabolic control as assessed by HbA1c. In both nicotinamide and control patients, no decline in C-peptide was detected 2 years after diagnosis, indicating that IIT preserves C-peptide secretion. We conclude that nicotinamide + IIT at diagnosis of DM1 prolonged for up to 2 years can be recommended, but longer follow-up is required to determine whether nicotinamide should be continued beyond this period.

Adolescent↗
PubMed1984

Nicotinamide does not protect islet B-cell metabolism against alloxan toxicity.

Nicotinamide, a poly(ADP-ribose)synthetase inhibitor, protected NMRI mice against alloxan-induced hyperglycemia when given 10 min before, but not 10 min after, the injection of the drug. Pretreatment in vivo with nicotinamide induced hyperglycemia at the time of alloxan injection, and this could account for the protective action of nicotinamide against alloxan diabetes. Exposure of islets to alloxan (2 mM) in vitro caused a marked inhibition of both glucose-stimulated proinsulin biosynthesis and insulin release, and this was not affected by the action of nicotinamide. Alloxan-impaired islet glucose oxidation was partly restored by nicotinamide. The decreased islet content of NADH plus NAD, which was observed after alloxan treatment, could be prevented by nicotinamide. Glucose-stimulated islet oxygen uptake was abolished after treatment with alloxan, and nicotinamide had no protective effect in this process. Leucine (10 mM) plus glutamine (10 mM), however, were still able to evoke an islet respiratory response after alloxan exposure. Alloxan caused an immediate increase in the islet efflux of radiolabeled nucleotides, which was followed after about 5 min by a further increase. This latter increase of the radio efflux was inhibited by the addition of nicotinamide. The inability of nicotinamide to prevent the alloxan-induced impairment of proinsulin biosynthesis, insulin release, and oxygen uptake, together with the failure of nicotinamide to prevent the development of diabetes when given after alloxan, does not support a current hypothesis that the major cytotoxic effect of alloxan is primarily due to DNA damage. The present data suggest that organelles other than the nuclei, e.g., the mitochondria or the plasma membrane, are the primary sites of B-cell injury by alloxan.(ABSTRACT TRUNCATED AT 250 WORDS)

Alloxan↗
PubMed1996

Effects of nicotinamide on milk composition and production in dairy cows fed supplemental fat.

Thirty-two cows, averaging 112 DIM, were assigned to four dietary treatments: 1) control, 2) Ca salts of fatty acids, 3) nicotinamide, and 4) Ca salts of fatty acids blended with nicotinamide during manufacture. Preliminary studies showed that nicotinamide survives blending with Ca salts of fatty acids during manufacture and that a blended mixture of nicotinamide and Ca salts of fatty acids gave results similar to those from nicotinamide plus Ca salts of fatty acids supplemented separately. Calcium salts of fatty acids increased milk fat percentage, decreased milk protein percentage, but had no effect on production of milk, FCM, fat, or protein. Nicotinamide increased production of milk and protein, decreased fat percentage, but had no effect on either production of FCM and protein or percentage of protein. Calcium salts of fatty acids increased NEFA in blood, and dietary nicotinamide increased concentrations of nicotinamide in blood, but glucose and BHBA in blood were unaffected by either dietary ingredient. Therefore, in these midlactation cows, the decreased milk protein percentage caused by supplemental dietary fat was prevented by nicotinamide. Supplementation with only nicotinamide increased total production of milk protein.

3-Hydroxybutyric Acid↗
PubMed1996

Nicotinamide as a repair inhibitor in vivo: studies using single and fractionated X-ray doses in mouse skin and kidneys.

Inhibitors of adenosine diphosphoribosyl transferase, like nicotinamide, 3-aminobenzamide and other analogues, can inhibit repair of radiation-induced sublethal and/or potentially lethal damage in some in vitro systems. Therefore, we have tested the effect of nicotinamide on repair parameters in vivo in two rodent normal tissues. In skin, the sensitivity to dose fractionation (1, 2, 5 or 10 X-ray fractions in 5 days) was monitored by defining the alpha/beta ratio in the presence or absence of nicotinamide (0.5 mg g-1) in air or carbogen. Pre- and postirradiation sensitization were investigated using an X-ray schedule of 5 fractions/5 days in carbogen alone or combined with nicotinamide given 1 h before, immediately after or 8 h after irradiation. Also, changes in the steepness of the underlying X-ray survival curve for the target skin clonogens, reflected by a change in the alpha/beta ratio, were investigated using the neutron top-up design. Underlying survival curves for oxygen +/- nicotinamide were obtained over the X-ray dose range 2.5 to 25 Gy, by administering single X-ray doses and following these with single top-up doses of d(4)-Be neutrons. Finally, in mouse kidney, recovery half-times (t1/2) were obtained by determining the time-dependent disappearance of X-ray damage using a split-dose design of two 6-Gy fractions separated by an interval which varied from 0 to 48 h and followed by two top-up doses from a neutron beam. No increase in alpha/beta for epidermal damage was seen with nicotinamide alone and, although sensitization was observed when the drug was given 1 h before irradiation, no postirradiation sensitization was detected. In kidney, there was no significant difference in the proportion of total repairable damage or in the half-life of recovery between treatments given with or without nicotinamide. Therefore, no decrease in normal tissue tolerance should be observed with the use of nicotinamide in clinical radiotherapy resulting either from reduced sparing with dose fractionation or from an increase in residual damage when shortening the interfraction interval. Finally, unless repair of radiation damage in normal tissues in vivo differs markedly from that of tumors, it is unlikely that the large sensitization seen in rodent tumors at 1.5 to 2 Gy per fraction, with carbogen and nicotinamide, can be attributed to nicotinamide acting as a repair inhibitor.

Animals↗
PubMed2006

Identification of nicotinamide N-methyltransferase as a novel tumor marker for renal clear cell carcinoma.

PURPOSE: To explore the involvement of enzymes of drug metabolism in renal cell carcinoma we analyzed the gene expression profiles of tumor and nontumor tissues from the same patient by DNA macroarray. The enzyme nicotinamide N-methyltransferase was selected for further evaluation. MATERIALS AND METHODS: Nicotinamide N-methyltransferase mRNA expression was investigated in paired tissue samples from cancerous and noncancerous parts of the kidneys of 30 patients with clear cell renal cell carcinoma who underwent tumor nephrectomy. Measurements were performed by semiquantitative reverse transcriptase-polymerase chain reaction and quantitative real-time polymerase chain reaction. Paired tissue samples were also obtained from 1 patient with chromophobe renal cell carcinoma and from another with oncocytoma to compare the specificity of changes in nicotinamide N-methyltransferase expression among tumors that are related to different renal epithelial cell types. Western blot analysis and catalytic activity assay were also performed to study nicotinamide N-methyltransferase expression. Expression correlated with tumor characteristics. RESULTS: A marked increased expression in tumor tissue was found for nicotinamide N-methyltransferase, which is an enzyme involved in the biotransformation of many drugs and xenobiotic compounds. Differential gene expression measurements in tumor vs normal tissue revealed up-regulation in all clear cell renal cell carcinomas at between 3 and 294-fold (mean 41). In contrast, in chromophobe renal cell carcinoma and oncocytoma nicotinamide N-methyltransferase expression did not increase. In addition, nicotinamide N-methyltransferase expression significantly correlated inversely with tumor size. CONCLUSIONS: Our results indicate that a marked nicotinamide N-methyltransferase increase is a peculiar feature of clear cell renal cell carcinoma. Additional studies may establish the role of nicotinamide N-methyltransferase in tumor formation and progression.

Adult↗
PubMed1994

Elevated expression of the Cyp1a2 gene in the presence of nicotinamide by adult mouse hepatocytes in primary culture.

Effects of nicotinamide on expression of Cyp1a1 and Cyp1a2 genes were investigated in adult C57BL/6NCrj mouse hepatocytes in primary culture. The cells were cultivated for up to 8 days as monolayers or spheroids (multicellular aggregates), respectively, on collagen-coated or noncoated dishes. CYP1A1 mRNA was prominently induced after exposure to 3-methylcholanthrene (MCA) throughout the observation period with either type of culture. In monolayer-cultured cells, substantial induction of CYP1A2 mRNA by MCA was observed only at day 1 of cultivation, followed by a decrease to very low levels thereafter. In contrast, prominent elevation of both mRNA species in spheroid culture was observed throughout the 8-day experimental period. In the presence of nicotinamide, the decrease in expression of CYP1A2 mRNA in monolayer-cultured hepatocytes was restored concentration-dependently and at 10 mM nicotinamide the induced amounts were equivalent to those observed in spheroid cells. Nicotinamide also elevated CYP1A2 mRNA expression in spheroid culture, but in both cases induction of CYP1A1 mRNA decreased. Constitutive expression of CYP1A2 mRNA in monolayer culture rapidly decreased with increasing culture period, but addition of nicotinamide likewise inhibited the decrease. Nicotinamide also restored considerable expression of CYP1A2 mRNA when not present from the start of cultivation, but added 24 h before. Activities of aryl hydrocarbon hydroxylase (AHH) and acetanilide-4-hydroxylase (AAH) were elevated with either type of culture after treatment with MCA and the presence of nicotinamide further increased the AAH, resulting in an increment in the activity ratio of AAH vs AHH. Intracellular contents of NAD were considerably elevated by addition of nicotinamide. However, isonicotinamide, which is not converted to NAD in the cell, also elevated CYP1A2 mRNA expression prominently. Furthermore, NAD contents in spheroid culture were not higher than those in monolayer culture. These observations indicate that the presence of nicotinamide in the medium restores constitutive and inducible expression of Cyp1a2 gene, independent of NAD, and thus the compound is useful for studying the underlying mechanism of regulation of this gene in adult mouse hepatocytes in monolayer culture.

Animals↗