SIRT2 (EC50 = 2 μM); SIRT1 (EC50 = 50~180 μM)

Type 2 diabetes was induced in Wistar rats by streptozotocin followed by nicotinamide. Test compounds and standard treatment were continued for 15 days. Results showed that there was significant normalisation of liver antioxidant enzymes compared to diabetic rats, suggesting all the tested compounds were beneficial in reducing oxidative stress

The Saccharomyces cerevisiae Sir2 protein is an NAD(+)-dependent histone deacetylase that plays a critical role in transcriptional silencing, genome stability, and longevity. A human homologue of Sir2, SIRT1, regulates the activity of the p53 tumor suppressor and inhibits apoptosis. The Sir2 deacetylation reaction generates two products: O-acetyl-ADP-ribose and nicotinamide, a precursor of nicotinic acid and a form of niacin/vitamin B(3). We show here that nicotinamide strongly inhibits yeast silencing, increases rDNA recombination, and shortens replicative life span to that of a sir2 mutant. Nicotinamide abolishes silencing and leads to an eventual delocalization of Sir2 even in G(1)-arrested cells, demonstrating that silent heterochromatin requires continual Sir2 activity. We show that physiological concentrations of nicotinamide noncompetitively inhibit both Sir2 and SIRT1 in vitro. The degree of inhibition by nicotinamide (IC(50) < 50 microm) is equal to or better than the most effective known synthetic inhibitors of this class of proteins. We propose a model whereby nicotinamide inhibits deacetylation by binding to a conserved pocket adjacent to NAD(+), thereby blocking NAD(+) hydrolysis. We discuss the possibility that nicotinamide is a physiologically relevant regulator of Sir2 enzymes.

Absorption, Distribution and Excretion
14C niacinamide was added to a water-in-oil (o/w) skin cream and 30% (w/w) soap base, and applied to the skin of female Colworth Wistar rats. The final concentration of niacinamide in the soap base solution was approximately 0.3% (w/v), and the final concentration of niacinamide in the skin cream was 1% (w/w). The skin cream and soap base paste were applied to the rat skin at an amount of approximately 20 mg/cm². The skin cream was carefully massaged into a 10 cm² area of skin for no more than 5 minutes, and then covered with a polyethylene-lined occlusive protective patch. The rats were placed in metabolic cages for 48 hours, during which all excrement was collected. After 48 hours, the animals were sacrificed, and the 14C content of the patch, the carcass, and the treated skin areas was determined. In the feces and carcasses of rats treated with a skin cream containing nicotinamide 14C, the recovered 14C content was as high as 32%; in rats treated with soap cream, the recovered 14C content was as high as 30%. Nicotinamide is effectively absorbed from the gastrointestinal tract. At low doses, absorption is mainly mediated by sodium-dependent facilitated diffusion. At high doses, passive diffusion is the main absorption mechanism. Up to 3 to 4 grams of nicotinamide are almost completely absorbed. Nicotinamide is transported to the liver via the portal vein circulation and to all tissues throughout the body via systemic circulation. Nicotinamide mainly enters most cells via passive diffusion and enters erythrocytes via facilitated diffusion. Nicotinamide is widely distributed throughout the body. After oral administration, both nicotinic acid and nicotinamide are readily absorbed from the gastrointestinal tract; nicotinamide (currently discontinued in the US) is also readily absorbed from subcutaneous and intramuscular injection sites. For more complete data on the absorption, distribution, and excretion of nicotinamides (16 in total), please visit the HSDB record page. Metabolites/Metabolites As a coenzyme, daily intake of 12-18 mg of niacin is converted into nicotinamide; larger doses of niacin are converted to only small amounts. Nicotinamide is metabolized in the liver to N-methylnicotinamide, other N-methylated derivatives, and nicotinic acid (a glycine conjugate of nicotinic acid). These metabolites are excreted in the urine. After taking physiological doses of niacin or nicotinamide, only a small amount of nicotinamide is excreted unchanged in the urine; however, after taking larger doses, a higher proportion of niacin and nicotinamide are excreted unchanged. N1-methyl-4-pyridone-3-carboxamide was detected in the chromatogram of plasma extracts after oral administration of nicotinamide in two subjects.
6-Hydroxynicotinamide and 6-hydroxynicotinamide were detected as metabolites by comparing UV, IR, and mass spectra of urine after intraperitoneal injection of 14C-labeled nicotinamide or nicotinamide in rats.
N1-Methyl-4-pyridone-3-carboxamide, the major metabolite of nicotinamide and nicotinamide, has been found to be synthesized from N1-methylnicotinamide.
For more complete metabolite/metabolite data on nicotinamide (7 metabolites in total), please visit the HSDB record. Page.
Uremic toxins tend to accumulate in the blood due to overeating or poor kidney filtration. Most uremic toxins are metabolic waste products and are usually excreted in urine or feces.
Biological half-life
The mean half-lives after administration of 1 gram, 3 grams, or 6 grams of nicotinamide are 2.7 hours, 5.9 hours, and 8.1 hours, respectively.

Toxicity Summary
Identification and Uses: Nicotinamide is a white crystalline powder. It is used to prevent niacin deficiency and treat pellagra. Nicotinamide is also used as a hair and skin conditioner in cosmetics. It has been used to fortify bread, flour, and other cereal products. Nicotinamide is commonly added to animal feed. It is also used in multivitamin preparations. Nicotinamide and niacin have similar functions as vitamins because they can be interconverted in the body. Vitamin B3 is collectively referred to as both. Nicotinamide is a component of an important coenzyme involved in hydrogen transfer. Human Studies: In the human body, nicotinamide is essential for lipid metabolism, tissue respiration, and glycogenolysis. In the body, nicotinamide is converted from niacin. Additionally, some dietary tryptophan is oxidized to niacin in the body, and then further oxidized to nicotinamide. Nicotinamide can synthesize two coenzymes: nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). NAD and NADP act as hydrogen carrier molecules involved in glycogenolysis, tissue respiration, and lipid metabolism. A study involving six volunteers (single doses of 3 to 9 g/day) showed mild nicotinamide-related toxicities, primarily nausea. Researchers also investigated the effects of 2 mM nicotinamide on unplanned DNA synthesis in resting human lymphocytes. In cells treated with UV radiation or N-methyl-N-nitro-N-nitrosoguanidine, nicotinamide doubled unplanned DNA synthesis. Animal studies: Instillation of 0.1 g of nicotinamide into the rabbit eye caused reversible irritation. No sensitization was observed in guinea pigs. A single intraperitoneal injection of nicotinamide (100 mg/kg) in male rats significantly induced the activity of all components of the hepatic microsomal mixed-function oxidase system and drug-metabolizing enzymes. Twelve male rats were grouped and fed nicotinamide in their diet for 8 to 12 weeks. Adding 0.1% nicotinamide (100 mg/kg body weight/day) to the diet did not significantly change the growth rate of rats; adding 0.2% increased the growth rate; and adding 0.4% significantly reduced the growth rate. Growth in rats fed a 1% nicotinamide diet was almost completely inhibited. No carcinogenic effects were observed in mice fed a 1% nicotinamide diet throughout their lives. However, nicotinamide promoted diethylnitrosamine-induced renal tubular cell tumors in rats. In mice, nicotinamide at doses of 500–2000 mg/kg inhibited orientation reflexes and exploratory behavior, and exhibited anti-aggression and anticonvulsant effects. Nicotinamide supplementation in pregnant rats reduced genomic DNA methylation levels and genomic uracil content (uracil is a DNA diversity modifier) in the placenta and fetal liver, while betaine completely or partially inhibited these changes. Furthermore, nicotinamide supplementation induced tissue-specific alterations in the mRNA expression of genes encoding nicotinamide N-methyltransferase, DNA methyltransferase 1, catalase, and the tumor protein p53 in the placenta and fetal liver. High-dose nicotinamide supplementation increased fetal hepatic alpha-fetoprotein mRNA levels, while betaine supplementation inhibited this increase. This leads to the conclusion that maternal nicotinamide supplementation can induce fetal epigenetic modifications and alterations in DNA base composition. In Ames tests using Salmonella TA 98, TA 100, TA 1535, TA 1537, and TA 1538 strains, nicotinamide was negative regardless of metabolic activation. Nicotinamide was not mutagenic to Saccharomyces cerevisiae D4 strain. It has been reported that nicotinamide at a concentration of 3 mg/mL (25 mM) can induce large chromosomal structural aberrations in Chinese hamster ovary cells in vitro. Uremic toxins (such as nicotinamide) are actively transported to the kidneys via organic ion transporters, particularly OAT3. Elevated uremic toxin levels can stimulate the production of reactive oxygen species. This appears to be mediated by the direct binding of uremic toxins to or inhibition of NADPH oxidases (especially NOX4, which is abundant in the kidneys and heart) (A7868). Reactive oxygen species (ROS) can induce various DNA methyltransferases (DNMTs) involved in the silencing of KLOTHO protein. KLOTHO has been shown to play important roles in anti-aging, mineral metabolism, and vitamin D metabolism. Multiple studies have shown that in acute or chronic kidney disease, KLOTHO mRNA and protein levels are decreased due to elevated local ROS levels (A7869).

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Interactions
Addition of 0.5 mg nicotinamide reduced the effect of phosphorus dichlorophosphate on cultured chicken embryo tibia.
Nicolatinamide prevented alkylating agents from depleting NAD coenzymes.
Nicolatinamide significantly reduced the carcinogenic activity of streptozotocin in the kidneys of male rats.
Oral or intravenous administration of nicotinamide prevented streptozotocin-induced diabetes in rhesus monkeys and dogs.
For more complete data on nicotinamide interactions (out of 25), please visit the HSDB records page.

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Non-human toxicity values
Oral LD50 in rats: 3500 mg/kg
Subcutaneous LD50 in rats: 1680 mg/kg
Oral LD50 in mice: 2500 mg/kg
Intraperitoneal LD50 in mice: 2050 mg/kg
For more complete non-human toxicity data for nicotinamide (9 types in total), please visit the HSDB record page.

J Biol Chem.2002 Nov 22;277(47):45099-107.

Nicotinamide is a white powder. (NTP, 1992)
Nicotinamide is a pyridine carboxamide with a pyridine structure in which the hydrogen at the 3-position is replaced by a formamide group. It has multiple functions, including as an EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor, metabolite, cofactor, antioxidant, neuroprotective agent, EC 3.5.1.98 (histone deacetylase) inhibitor, anti-inflammatory agent, Sir2 inhibitor, Saccharomyces cerevisiae metabolite, Escherichia coli metabolite, mouse metabolite, human urine metabolite, and anti-aging agent. It is a vitamin B3, pyridine carboxamide, and pyridine alkaloid. It is functionally related to nicotinic acid.
It is an important compound and a component of the coenzyme NAD. Its main role is in the prevention and/or treatment of black tongue and pellagra. Most animals cannot synthesize sufficient amounts of this compound to prevent nutritional deficiencies and therefore must be obtained through dietary supplementation. Nicotinamide is a metabolite found in or produced by Escherichia coli (K12 strain, MG1655 strain). It has also been reported in Lactobacillus, Taraxacum mongolicum, and other organisms with relevant data. Nicotinamide is the active form of vitamin B3 and a component of the coenzyme nicotinamide adenine dinucleotide (NAD). Nicotinamide acts as a sensitizer for chemotherapy and radiotherapy by enhancing tumor blood flow, thereby reducing tumor hypoxia. The drug also inhibits poly(ADP-ribose) polymerase, an enzyme involved in repairing DNA strand breaks caused by radiation or chemotherapy. Nicotinamide is a uremic toxin. Based on their chemical and physical properties, uremic toxins can be classified into three main categories: 1) small, water-soluble, non-protein-bound compounds, such as urea; 2) small, lipid-soluble and/or protein-bound compounds, such as phenols; and 3) larger, so-called medium-molecule compounds, such as β2-microglobulins. Long-term exposure to uremic toxins can lead to various diseases, including kidney damage, chronic kidney disease, and cardiovascular disease. Nicotinamide, or vitamin B3, is an important compound and a component of the coenzyme NAD. Its main function is to prevent and/or treat black tongue and pellagra. Most animals cannot synthesize enough nicotinamide to prevent nutritional deficiencies and therefore must obtain it through dietary supplementation. Nicotinamide is used to enhance the effectiveness of radiotherapy against tumor cells. While both niacin (nicotinic acid) and nicotinamide belong to vitamin B3, they have different uses. Nicotinamide can be used to treat arthritis and early-onset type 1 diabetes, while niacin is effective in lowering high cholesterol levels. Nicotinamide is a metabolite of Saccharomyces cerevisiae, present in or produced by the yeast. It is an important compound and a component of the coenzyme NAD. Its main function is to prevent and/or treat black tongue and pellagra. Most animals cannot synthesize enough nicotinamide themselves to prevent nutritional deficiencies and therefore must obtain it through dietary supplementation. See also: ascorbic acid nicotinamide (its active ingredient); dapsone; nicotinamide (its ingredient); adenosine; nicotinamide (its ingredient)... See more...

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Therapeutic Uses
B Vitamins
/Clinical Trials/ ClinicalTrials.gov is a registry and results database that lists human clinical studies funded by public and private institutions worldwide. The website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov contains a summary of the study protocol, including: the disease or condition; the intervention (e.g., the medical product, behavior, or procedure being studied); the title, description, and design of the study; participation requirements (eligibility criteria); the location where the study was conducted; contact information for the study location; and links to relevant information from other health websites, such as the NLM's MedlinePlus (for patient health information) and PubMed (for citations and abstracts of academic articles in the medical field). Nicotinamide is listed in the database.
Niacin and nicotinamide are used to prevent niacin deficiency and treat pellagra. Some clinicians prefer to use nicotinamide to treat pellagra because it does not have a vasodilatory effect. Pellagra may be caused by dietary deficiencies, isoniazid treatment, or reduced conversion of tryptophan to nicotinic acid in Hartnap disease or carcinoid tumors. /Listed on US Product Label/
Although there are not sufficient controlled trials to confirm the therapeutic value of nicotinic acid and nicotinamide, these drugs have been used to treat schizophrenia, drug-induced hallucinations, chronic brain syndromes, ADHD, unipolar depression, motion sickness, alcohol dependence, livedo reticulovar vasculitis, acne, and leprosy. /Not Included on US Product Label/
For more complete data on the therapeutic uses of nicotinamide (14 in total), please visit the HSDB record page.

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Drug Warnings
Patients taking nicotinic acid or nicotinamide should monitor their blood glucose levels regularly, especially at the beginning of treatment. Dosage requirements for antidiabetic medications (such as insulin, oral sulfonylureas) may vary in patients with diabetes.
Potential adverse effects on the fetus: Fetal drug concentrations are higher than those in the mother, but no fetal malformations have been reported. Potential side effects in breastfed infants: No adverse reactions are currently known. FDA Classification: C (C = Laboratory animal studies have shown adverse effects on the fetus (teratogenicity, embryonic lethality, etc.), but there are no controlled studies in pregnant women. Despite the potential risks, the benefits of using this drug in pregnant women may be acceptable, or there are no adequate laboratory animal studies or studies in pregnant women.) /Excerpt from Table II/
Nicotinamide is administered daily in liquid form for patients with head and neck cancer receiving 5 to 7 weeks of radiation therapy. Nicotinamide is taken orally 1.5 hours before irradiation. The daily dose is 80 mg/kg body weight, with a maximum dose of 6 g. For patients experiencing serious side effects, the dose is reduced to 60 mg/kg. …Monitor for side effects of nicotinamide. All patients achieved peak plasma concentrations above 700 nM/mL within 0.25 to 3 hours after administration. During the first week of treatment, 82% of samples had adequate plasma concentrations at irradiation. Nausea occurred in 65% of patients, with or without vomiting. Of the 7 patients, 6 showed improved tolerability after a 25% dose reduction, but 4 of them experienced plasma concentrations below 700 nM/mL at the time of irradiation. Other nicotinamide side effects included gastrointestinal symptoms, flushing, dizziness, sweating, fatigue, and headache. The strongest predictor of severe nicotinamide toxicity was the mean plasma concentration measured during the first week of irradiation. Abnormal liver function tests (including elevated serum bilirubin, AST [SGOT], ALT [SGPT], and LDH levels), jaundice, and chronic liver injury have been reported during nicotinic acid and nicotinamide treatment. Prothrombin time abnormalities and hypoalbuminemia have also been reported. For more complete data on nicotinamide (6 in total), please visit the HSDB record page.

C6H6N2O

122.12

122.048

C, 59.01; H, 4.95; N, 22.94; O, 13.10

98-92-0

25334-23-0; Nicotinamide;98-92-0

936

White to off-white solid

1.2±0.1 g/cm3

257.7±32.0 °C at 760 mmHg

128-131 °C(lit.)

109.7±25.1 °C

0.0±0.6 mmHg at 25°C

1.590

Endogenous Metabolite

-0.24

1

2

1

9

114

0

O=C(C1=C([H])N=C([H])C([H])=C1[H])N([H])[H]

DFPAKSUCGFBDDF-UHFFFAOYSA-N

InChI=1S/C6H6N2O/c7-6(9)5-2-1-3-8-4-5/h1-4H,(H2,7,9)

3-Pyridinecarboxylic acid amide

2934.99.03.00

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)