Chemistry:Nicotinamide

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Short description: Dietary supplement and medication
Nicotinamide
Nicotinamid.svg
Nicotinamide-from-xtal-2011-Mercury-3D-sf.png
Clinical data
Pronunciation/ˌnaɪəˈsɪnəmaɪd/, /ˌnɪkəˈtɪnəmaɪd/
Other namesNAM, 3-pyridinecarboxamide
niacinamide
nicotinic acid amide
vitamin PP
nicotinic amide
vitamin B3
AHFS/Drugs.comConsumer Drug Information
License data
Routes of
administration		By mouth, topical
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC6H6N2O
Molar mass122.127 g·mol−1
3D model (JSmol)
Density1.40 g/cm3 g/cm3 [1]
Melting point129.5 °C (265.1 °F)
Boiling point334 °C (633 °F)

Niacinamide or nicotinamide is a form of vitamin B3 found in food and used as a dietary supplement and medication.[2][3][4] As a supplement, it is used by mouth to prevent and treat pellagra (niacin deficiency).[3] While nicotinic acid (niacin) may be used for this purpose, niacinamide has the benefit of not causing skin flushing.[3] As a cream, it is used to treat acne, and has been observed in clinical studies to improve the appearance of aging skin by reducing hyperpigmentation and redness.[4][5] It is a water-soluble vitamin. Niacinamide is the supplement name, while nicotinamide is the scientific name.

Side effects are minimal.[6][7] At high doses, liver problems may occur.[6] Normal amounts are safe for use during pregnancy.[8] Niacinamide is in the vitamin B family of medications, specifically the vitamin B3 complex.[9][10] It is an amide of nicotinic acid.[6] Foods that contain niacinamide include yeast, meat, milk, and green vegetables.[11]

Niacinamide was discovered between 1935 and 1937.[12][13] It is on the World Health Organization's List of Essential Medicines.[14][15] Niacinamide is available as a generic medication and over the counter.[9] Commercially, niacinamide is made from either nicotinic acid (niacin) or nicotinonitrile.[13][16] In some countries, grains have niacinamide added to them.[13]

Medical uses

Niacin deficiency

Niacinamide is the preferred treatment for pellagra, caused by niacin deficiency.[3]

Acne

Niacinamide cream is used as a treatment for acne.[4] It has anti-inflammatory actions, which may benefit people with inflammatory skin conditions.[17]

Niacinamide increases the biosynthesis of ceramides in human keratinocytes in vitro and improves the epidermal permeability barrier in vivo.[18] The application of 2% topical niacinamide for 2 and 4 weeks has been found to be effective in lowering the sebum excretion rate.[19] Niacinamide has been shown to prevent Cutibacterium acnes-induced activation of toll-like receptor 2, which ultimately results in the down-regulation of pro-inflammatory interleukin-8 production.[20]

Skin cancer

Niacinamide at doses of 500 to 1000 mg a day decreases the risk of skin cancers, other than melanoma, in those at high risk.[21]

Side effects

Niacinamide has minimal side effects.[6][7] At very high doses above 3g/ day acute liver toxicity has been documented in at least one case.[6] Normal doses are safe during pregnancy.[8]

Chemistry

The structure of nicotinamide consists of a pyridine ring to which a primary amide group is attached in the meta position. It is an amide of nicotinic acid.[6] As an aromatic compound, it undergoes electrophilic substitution reactions and transformations of its two functional groups. Examples of these reactions reported in Organic Syntheses include the preparation of 2-chloronicotinonitrile by a two-step process via the N-oxide,[22][23]

Nicotinamide to 2-chloronicotinonitrile.png

from nicotinonitrile by reaction with phosphorus pentoxide,[24] and from 3-aminopyridine by reaction with a solution of sodium hypobromite, prepared in situ from bromine and sodium hydroxide.[25]

NAD+, the oxidized form of NADH, contains the nicotinamide moiety (highlighted in red)

Industrial production

The hydrolysis of nicotinonitrile is catalysed by the enzyme nitrile hydratase from Rhodococcus rhodochrous J1,[26][27][16] producing 3500 tons per annum of nicotinamide for use in animal feed.[28] The enzyme allows for a more selective synthesis as further hydrolysis of the amide to nicotinic acid is avoided.[29][30] Nicotinamide can also be made from nicotinic acid. According to Ullmann's Encyclopedia of Industrial Chemistry, worldwide 31,000 tons of nicotinamide were sold in 2014.[13]

Biochemistry

The active Nicotinamide group on the molecule NAD+ undergoes oxidation in many metabolic pathways.

Nicotinamide, as a part of the cofactor nicotinamide adenine dinucleotide (NADH / NAD+) is crucial to life. In cells, nicotinamide is incorporated into NAD+ and nicotinamide adenine dinucleotide phosphate (NADP+). NAD+ and NADP+ are cofactors in a wide variety of enzymatic oxidation-reduction reactions, most notably glycolysis, the citric acid cycle, and the electron transport chain.[31] If humans ingest nicotinamide, it will likely undergo a series of reactions that transform it into NAD, which can then undergo a transformation to form NADP+. This method of creation of NAD+ is called a salvage pathway. However, the human body can produce NAD+ from the amino acid tryptophan and niacin without our ingestion of nicotinamide.[32]

NAD+ acts as an electron carrier that mediates the interconversion of energy between nutrients and the cell's energy currency, adenosine triphosphate (ATP). In oxidation-reduction reactions, the active part of the cofactor is the nicotinamide. In NAD+, the nitrogen in the aromatic nicotinamide ring is covalently bonded to adenine dinucleotide. The formal charge on the nitrogen is stabilized by the shared electrons of the other carbon atoms in the aromatic ring. When a hydride atom is added onto NAD+ to form NADH, the molecule loses its aromaticity, and therefore a good amount of stability. This higher energy product later releases its energy with the release of a hydride, and in the case of the electron transport chain, it assists in forming adenosine triphosphate.[33]

When one mole of NADH is oxidized, 158.2 kJ of energy will be released.[33]

Biological role

Nicotinamide occurs as a component of a variety of biological systems, including within the vitamin B family and specifically the vitamin B3 complex.[9][10] It is also a critically important part of the structures of NADH and NAD+, where the N-substituted aromatic ring in the oxidised NAD+ form undergoes reduction with hydride attack to form NADH.[31] The NADPH/NADP+ structures have the same ring, and are involved in similar biochemical reactions.

Nicotinamide can be methylated in the liver to biologically active 1-Methylnicotinamide when there's sufficient methyl donors.

Food sources

Niacinamide occurs in trace amounts mainly in meat, fish, nuts, and mushrooms, as well as to a lesser extent in some vegetables.[34] It is commonly added to cereals and other foods. Many multivitamins contain 20–30 mg of vitamin B3 and it is also available in higher doses.[35]

Compendial status

  • British Pharmacopoeia[36]
  • Japanese Pharmacopoeia[37]

Research

A 2015 trial found niacinamide to reduce the rate of new nonmelanoma skin cancers and actinic keratoses in a group of people at high risk for the conditions.[38]

Niacinamide has been investigated for many additional disorders, including treatment of bullous pemphigoid nonmelanoma skin cancers.[39]

Niacinamide may be beneficial in treating psoriasis.[40]

There is tentative evidence for a potential role of niacinamide in treating acne, rosacea, autoimmune blistering disorders, ageing skin, and atopic dermatitis.[39] Niacinamide also inhibits poly(ADP-ribose) polymerases (PARP-1), enzymes involved in the rejoining of DNA strand breaks induced by radiation or chemotherapy.[41] ARCON (accelerated radiotherapy plus carbogen inhalation and nicotinamide) has been studied in cancer.[42]

Research has suggested niacinamide may play a role in the treatment of HIV.[43]

References

  1. ↑ Record in the GESTIS Substance Database of the Institute for Occupational Safety and Health
  2. ↑ Nutritional Biochemistry of the Vitamins. Cambridge University Press. 2003. p. 203. ISBN 978-1-139-43773-8. https://books.google.com/books?id=umylV1Jbm4EC&pg=PA203. 
  3. ↑ 3.0 3.1 3.2 3.3 WHO Model Formulary 2008. World Health Organization. 2009. pp. 496, 500. ISBN 9789241547659. 
  4. ↑ 4.0 4.1 4.2 British National Formulary: BNF 69 (69th ed.). British Medical Association. 2015. p. 822. ISBN 978-0-85711-156-2. 
  5. ↑ "Niacinamide: A B vitamin that improves aging facial skin appearance". Dermatologic Surgery 31 (7 Pt 2): 860–5; discussion 865. July 2005. doi:10.1111/j.1524-4725.2005.31732. PMID 16029679. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 "Safety of high-dose nicotinamide: a review". Diabetologia 43 (11): 1337–45. November 2000. doi:10.1007/s001250051536. PMID 11126400. https://link.springer.com/content/pdf/10.1007%2Fs001250051536.pdf. Retrieved 20 April 2018. 
  7. ↑ 7.0 7.1 "Niacin: chemical forms, bioavailability, and health effects". Nutrition Reviews 70 (6): 357–66. June 2012. doi:10.1111/j.1753-4887.2012.00479.x. PMID 22646128. 
  8. ↑ 8.0 8.1 "Niacinamide Use During Pregnancy". https://www.drugs.com/pregnancy/niacinamide.html. 
  9. ↑ 9.0 9.1 9.2 "Niacinamide: Indications, Side Effects, Warnings". 6 June 2017. https://www.drugs.com/cdi/niacinamide.html. 
  10. ↑ 10.0 10.1 Nutrition for Healthy Skin: Strategies for Clinical and Cosmetic Practice. Springer Science & Business Media. 2010. p. 153. ISBN 9783642122644. https://books.google.com/books?id=rUNZHmpBu2sC&pg=PA153. 
  11. ↑ Tietz Textbook of Clinical Chemistry and Molecular Diagnostics (5th ed.). Elsevier Health Sciences. 2012. p. 934. ISBN 978-1-4557-5942-2. https://books.google.com/books?id=BBLRUI4aHhkC&pg=PA934. 
  12. ↑ Drug Discovery: A History. John Wiley & Sons. 2005. p. 231. ISBN 978-0-470-01552-0. https://books.google.com/books?id=jglFsz5EJR8C&pg=PA231. 
  13. ↑ 13.0 13.1 13.2 13.3 "Vitamins, 11. Niacin (Nicotinic Acid, Nicotinamide". Ullmann's Encyclopedia of Industrial Chemistry (6th ed.). Weinheim: Wiley-VCH. 2015. pp. 1–9. doi:10.1002/14356007.o27_o14.pub2. ISBN 978-3-527-30385-4. 
  14. ↑ World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO. 
  15. ↑ World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. 2021. WHO/MHP/HPS/EML/2021.02. 
  16. ↑ 16.0 16.1 "Enzymatic Synthesis of Amides". Biocatalysis in Organic Synthesis 1. Science of Synthesis. Georg Thieme Verlag. 2015. pp. 329–372. ISBN 9783131766113. https://books.google.com/books?id=8h_wBgAAQBAJ&pg=PA362. 
  17. ↑ "Pharmacologic doses of nicotinamide in the treatment of inflammatory skin conditions: a review". Cutis 77 (1 Suppl): 11–6. January 2006. PMID 16871774. 
  18. ↑ "Nicotinamide increases biosynthesis of ceramides as well as other stratum corneum lipids to improve the epidermal permeability barrier". The British Journal of Dermatology 143 (3): 524–31. September 2000. doi:10.1111/j.1365-2133.2000.03705.x. PMID 10971324. 
  19. ↑ "The effect of 2% niacinamide on facial sebum production". Journal of Cosmetic and Laser Therapy 8 (2): 96–101. June 2006. doi:10.1080/14764170600717704. PMID 16766489. 
  20. ↑ "Activation of toll-like receptor 2 in acne triggers inflammatory cytokine responses". Journal of Immunology 169 (3): 1535–41. August 2002. doi:10.4049/jimmunol.169.3.1535. PMID 12133981. 
  21. ↑ "Nicotinamide for photoprotection and skin cancer chemoprevention: A review of efficacy and safety". Experimental Dermatology 28 (Suppl 1): 15–22. February 2019. doi:10.1111/exd.13819. PMID 30698874. 
  22. ↑ "Nicotinamide-1-oxide". Organic Syntheses 37: 63. 1957. doi:10.15227/orgsyn.037.0063. http://www.orgsyn.org/demo.aspx?prep=CV4P0704. ; Collective Volume, 4, pp. 704 
  23. ↑ "2-Chloronicitinonitrile". Organic Syntheses 37: 12. 1957. doi:10.15227/orgsyn.037.0012. http://www.orgsyn.org/demo.aspx?prep=CV4P0166. ; Collective Volume, 4, pp. 166 
  24. ↑ "Nicotinonitrile". Organic Syntheses 33: 52. 1953. doi:10.15227/orgsyn.033.0052. http://www.orgsyn.org/demo.aspx?prep=CV4P0706. ; Collective Volume, 4, pp. 706 
  25. ↑ "3-Aminopyridine". Organic Syntheses 30: 3. 1950. doi:10.15227/orgsyn.030.0003. http://www.orgsyn.org/demo.aspx?prep=CV4P0045. ; Collective Volume, 4, pp. 45 
  26. ↑ "Nitrile Hydratase-Catalyzed Production of Nicotinamide from 3-Cyanopyridine in Rhodococcus rhodochrous J1". Applied and Environmental Microbiology 54 (7): 1766–1769. July 1988. doi:10.1128/AEM.54.7.1766-1769.1988. PMID 16347686. Bibcode: 1988ApEnM..54.1766N. 
  27. ↑ "Building Blocks". White Biotechnology. Advances in Biochemical Engineering / Biotechnology. 105. Springer Science & Business Media. 2007. 133–173. doi:10.1007/10_033. ISBN 9783540456957. https://books.google.com/books?id=_tXoG93OWHgC&pg=PA141. 
  28. ↑ "Hydrolysis of Nitriles to Amides". Biocatalysis in Organic Synthesis 1. Science of Synthesis. Georg Thieme Verlag. 2015. pp. 255–276. ISBN 9783131766113. https://books.google.com/books?id=8h_wBgAAQBAJ&pg=PA256. 
  29. ↑ "Biocatalysis". Green Chem. 1 (2): 99–106. 1999. doi:10.1039/A809538H. 
  30. ↑ "Historical Perspectives: Paving the Way for the Future". Biocatalysis in Organic Synthesis 1. Science of Synthesis. Georg Thieme Verlag. 2015. pp. 1–39. ISBN 9783131766113. https://books.google.com/books?id=8h_wBgAAQBAJ&pg=PA7. 
  31. ↑ 31.0 31.1 "NAD+ metabolism in health and disease". Trends in Biochemical Sciences 32 (1): 12–9. January 2007. doi:10.1016/j.tibs.2006.11.006. PMID 17161604. http://www.dartmouth.edu/~brenner/belenky07a.pdf. 
  32. ↑ "Parkinson's disease: the first common neurological disease due to auto-intoxication?". QJM 98 (3): 215–26. March 2005. doi:10.1093/qjmed/hci027. PMID 15728403. 
  33. ↑ 33.0 33.1 "Energy for the Body: Oxidative Phosphorylation". Department of Chemistry, Washington University in St. Louis. 5 September 2008. http://www.chemistry.wustl.edu/~edudev/LabTutorials/Cytochromes/cytochromes.html. 
  34. ↑ "A review of nicotinamide: treatment of skin diseases and potential side effects". Journal of Cosmetic Dermatology 13 (4): 324–8. December 2014. doi:10.1111/jocd.12119. PMID 25399625. 
  35. ↑ "Nicotinamide". DermNet New Zealand Trust. 2017. http://www.dermnetnz.org/topics/nicotinamide/. 
  36. ↑ British Pharmacopoeia Commission Secretariat (2009). Index, BP 2009. http://www.pharmacopoeia.co.uk/pdf/2009_index.pdf. Retrieved 4 February 2010. 
  37. ↑ Japanese Pharmacopoeia (15th ed.). 2006. http://jpdb.nihs.go.jp/jp15e/JP15.pdf. Retrieved 4 February 2010. 
  38. ↑ "Melanoma and nonmelanoma skin cancer chemoprevention: A role for nicotinamide?". Photodermatology, Photoimmunology & Photomedicine 34 (1): 5–12. January 2018. doi:10.1111/phpp.12328. PMID 28681504. 
  39. ↑ 39.0 39.1 "Nicotinamide and the skin". The Australasian Journal of Dermatology 55 (3): 169–75. August 2014. doi:10.1111/ajd.12163. PMID 24635573. 
  40. ↑ "Nicotinamide: a potential addition to the anti-psoriatic weaponry". FASEB Journal 17 (11): 1377–9. August 2003. doi:10.1096/fj.03-0002hyp. PMID 12890690. 
  41. ↑ "Definition of niacinamide". NCI Drug Dictionary. National Cancer Institute. 2 February 2011. http://www.cancer.gov/drugdictionary/?CdrID=42044. 
  42. ↑ "ARCON: a novel biology-based approach in radiotherapy". The Lancet. Oncology 3 (12): 728–37. December 2002. doi:10.1016/s1470-2045(02)00929-4. PMID 12473514. 
  43. ↑ "Patient Is Reported Free of H.I.V., but Scientists Urge Caution". 7 July 2020. https://www.nytimes.com/2020/07/07/health/hiv-remission-brazil.html. 

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