Nicotinamide

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Nicotinamide (INN, BAN Template:Abbr<ref name="Martindale37">Template:Cite book</ref>) or niacinamide (USAN Template:Abbr) is a form of vitamin B₃ found in food and used as a dietary supplement and medication.<ref>Template:Cite book</ref><ref name = WHO2008 /><ref name = BNF69>Template:Cite book</ref> As a supplement, it is used orally (swallowed by mouth) to prevent and treat pellagra (niacin deficiency).<ref name=WHO2008/> While nicotinic acid (niacin) may be used for this purpose, nicotinamide has the benefit of not causing skin flushing.<ref name=WHO2008>Template:Cite book</ref> 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.<ref name=BNF69/><ref>Template:Cite journal</ref> It is a water-soluble vitamin.

Side effects are minimal.<ref name=Kn2000/><ref name=Mac2012>Template:Cite journal</ref> At high doses, liver problems may occur.<ref name=Kn2000/> Normal amounts are safe for use during pregnancy.<ref name=Preg2016>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Nicotinamide is in the vitamin B family of medications, specifically the vitamin B₃ complex.<ref name=CDI2016>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name=Healthy-Skin>Template:Cite book</ref> It is an amide of nicotinic acid.<ref name=Kn2000>Template:Cite journal</ref> Foods that contain nicotinamide include yeast, meat, milk, and green vegetables.<ref>Template:Cite book</ref>

Nicotinamide was discovered between 1935 and 1937.<ref>Template:Cite book</ref><ref name=Ullmann2015/> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO21st">Template:Cite book</ref><ref name="WHO22nd">Template:Cite book</ref> Nicotinamide is available as a generic medication and over the counter.<ref name=CDI2016/> Commercially, nicotinamide is made from either nicotinic acid (niacin) or nicotinonitrile.<ref name = Ullmann2015/><ref name = Synthesis2015 /> In some countries, grains have nicotinamide added to them.<ref name=Ullmann2015>Template:Cite encyclopedia</ref>

Extra-terrestrial nicotinamide has been found in carbonaceous chondrite meteorites.<ref name="Oba2022">Template:Cite journal</ref>

Medical uses

Niacin deficiency

Nicotinamide is the preferred treatment for pellagra, caused by niacin deficiency.<ref name="WHO2008" />

Acne

Nicotinamide cream is used as a treatment for acne.<ref name="BNF69" /> It has anti-inflammatory actions, which may benefit people with inflammatory skin conditions.<ref>Template:Cite journal</ref>

Nicotinamide increases the biosynthesis of ceramides in human keratinocytes in vitro and improves the epidermal permeability barrier in vivo.<ref>Template:Cite journal</ref> The application of 2% topical nicotinamide for 2 and 4 weeks has been found to be effective in lowering the sebum excretion rate.<ref>Template:Cite journal</ref> Nicotinamide 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.<ref>Template:Cite journal</ref>

Skin cancer

Nicotinamide at doses of 500 to 1000Template:Nbspmg a day decreases the risk of skin cancers, other than melanoma, in those at high risk.<ref>Template:Cite journal</ref>

Side effects

Nicotinamide has minimal side effects.<ref name=Kn2000/><ref name=Mac2012 /> At very high doses above 3g/ day acute liver toxicity has been documented in at least one case.<ref name=Kn2000/> Normal doses are safe during pregnancy.<ref name=Preg2016 />

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.<ref name=Kn2000/> 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,<ref>Template:OrgSynth</ref><ref>Template:OrgSynth</ref>

File:Nicotinamide to 2-chloronicotinonitrile.png

from nicotinonitrile by reaction with phosphorus pentoxide,<ref>Template:OrgSynth</ref> and from 3-aminopyridine by reaction with a solution of sodium hypobromite, prepared in situ from bromine and sodium hydroxide.<ref>Template:OrgSynth</ref>

File:Nicotinamide highlighted in NAD+.svg

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,<ref>Template:Cite journal</ref><ref>Template:Cite book</ref><ref name=Synthesis2015>Template:Cite book</ref> producing 3500 tons per annum of nicotinamide for use in animal feed.<ref>Template:Cite book</ref> The enzyme allows for a more selective synthesis as further hydrolysis of the amide to nicotinic acid is avoided.<ref>Template:Cite journal</ref><ref>Template:Cite book</ref> 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.<ref name=Ullmann2015/>

Biochemistry

File:NAD+ Oxidation and Reduction.png

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.<ref name="Belenky">Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>

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.<ref name="Oxidative Phosphorylation">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

When one mole of NADH is oxidized, 158.2Template:NbspkJ of energy will be released.<ref name="Oxidative Phosphorylation"/>

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.<ref name="CDI2016" /><ref name="Healthy-Skin" /> 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.<ref name="Belenky" /> 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 are sufficient methyl donors.

Food sources

Nicotinamide occurs in trace amounts mainly in meat, fish, nuts, and mushrooms, as well as to a lesser extent in some vegetables.<ref>Template:Cite journal</ref> It is commonly added to cereals and other foods. Many multivitamins contain 20–30Template:Nbspmg of vitamin B₃ and it is also available in higher doses.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Compendial status

• British Pharmacopoeia<ref name=ib29>Template:Cite book</ref>
• Japanese Pharmacopoeia<ref name=jp15>Template:Cite book</ref>

Research

A 2015 trial found nicotinamide to reduce the rate of new nonmelanoma skin cancers and actinic keratoses in a group of people at high risk for the conditions.<ref>Template:Cite journal</ref>

Nicotinamide has been investigated for many additional disorders, including treatment of bullous pemphigoid and nonmelanoma skin cancers.<ref name = "Chen_2014">Template:Cite journal</ref>

Nicotinamide may be beneficial in treating psoriasis.<ref>Template:Cite journal</ref>

There is tentative evidence for a potential role of nicotinamide in treating acne, rosacea, autoimmune blistering disorders, ageing skin, and atopic dermatitis.<ref name = "Chen_2014"/> Nicotinamide also inhibits poly(ADP-ribose) polymerases (PARP-1), enzymes involved in the rejoining of DNA strand breaks induced by radiation or chemotherapy.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> ARCON (accelerated radiotherapy plus carbogen inhalation and nicotinamide) has been studied in cancer.<ref name="Kaanders2002">Template:Cite journal</ref>

Research has suggested nicotinamide may play a role in the treatment of HIV.<ref>Template:Cite news</ref>

Extra-terrestrial occurrence

Extra-terrestrial nicotinamide has been found in carbonaceous chondrite meteorites.

Vitamin B3 vitamers from extra-terrestrial sources

Meteorite	Nicotinic acid	Nicotinamide
Orgueil<ref name="Oba2023">Template:Cite journal</ref>	715ppb	214ppb
Murray<ref name="Oba2022"></ref>	626ppb	65ppb
Murchison	2.4 nmol/g<ref name=",<ref name="Glavin2025">Template:Cite journal</ref> 190ppb<ref name="Oba2022"></ref>	16ppb<ref name="Oba2022"></ref>
Tagish Lake<ref name="Oba2022"></ref>	108ppb	5ppb