Nicotinamide is also commercially available in vitamin supplements and in a range of cosmetic, hair, and skin preparations. Nicotinamide is the primary precursor of nicotinamide adenine dinucleotide (NAD+), an essential coenzyme in ATP production and the sole substrate of the nuclear enzyme poly-ADP-ribose polymerase-1 (PARP-1). This study shows the role of nicotinamide in the protection from carcinogenesis, DNA repair, and maintenance of genomic stability. Some cosmetic preparations also contain nicotinamide. Systemic absorption of topical nicotinamide has been reported to be approximately 10% depending on the vehicle used. Adverse effects of nicotinamide are rare and have occurred mainly with high oral doses (≥6 gram/day), which include nausea, vomiting, liver toxicity, headache, fatigue, and dizziness. Unlike niacin, nicotinamide is not a vasodilator, thus it rarely causes flushing. Severe nicotinamide deficiency in humans causes the disease pellagra (Italian “pelle agra”; “rough skin”), which is characterised by photosensitive dermatitis, diarrhoea, dementia, and death [3]. It was thought that the clinical manifestations of pellagra arise from the deficient NAD and NADP levels in maintaining energy for cellular functions.

Nicotinamide: Photoimmunosuppression and Skin Cancer - The immune system is an important defense mechanism that prevents potentially cancerous cells from developing into tumors. In humans, the importance of immunity in preventing cancer is observed in renal transplant recipients on immunosuppressive medications. In this population, there is an increased incidence of all cancer type (13.7-fold increase), nonmelanoma skin cancer (33-fold increase), and melanoma (3.3-fold increase) compared to age-matched immune competent individuals. Ultraviolet (UV) radiation in sunlight is the primary initiator of skin cancer by causing DNA damage in the skin and by suppressing cutaneous immunity, even at exposure doses 25% to 50% of those required to cause mild sunburn. Both UVB (290– 320 nm) and UVA (320–400 nm) in sunlight are immune suppressive. UV-induced DNA damage, particularly in the form of cyclobutane pyrimidine dimers (CPDs), is an important molecular trigger for UV-induced immunosuppression. Agents that can modulate DNA repair and prevent UV-induced immunosuppression may thus reduce skin cancer.

Conclusion: Nicotinamide, which is the dietary precursor for NAD provides a substrate for PARP-1 activity. The activation of nuclear enzyme PARP-1 by DNA strand breaks during cellular genotoxic stress responses leads to complex signaling pathway that can enhance DNA repair, result in apoptotic cell death, or cause cellular energy loss leading to necrotic cell death. In vivo and in vitro studies showed that NAD content of the cells influences responses to DNA damaging agents. NAD depletion impairs ADP-ribose polymer metabolism and increases genomic instability in the face of genotoxic and oxidative stress challenges. Nicotinamide deficiency in humans may also contribute to increased frequency of gastrointestinal cancers in certain populations although other micronutrient deficiencies are likely to be involved as well. Nicotinamide supplementation in animal models has opposing effect on carcinogenesis, depending on the type of carcinogens and target organs. Nicotinamide protected against UV-induced immunosuppression in mice and humans and UV-induced carcinogenesis in mice. Limited study in humans indicates that skin NAD content is an important determinant of malignant phenotype. Thus, nicotinamide supplementation may influence the progression of premalignant actinic keratoses to malignant squamous cell cancers. PARP-1 plays a key role in regulation of genes involved in inflammation, apoptosis, and cellular differentiation. While PARP-1 inhibition could impair its role in DNA repair, PARP-1 overactivation is detrimental to the cells by depleting its substrate NAD, which leads to cellular energy crisis and necrotic cell death. In various murine models, PARP-1 inhibition was shown to favor apoptotic cell death, reduce inflammatory response, and reduce genomic sensitivity to various carcinogens. However, extrapolation of these data to human, particularly when physiological regimes involved in human carcinogenesis, should be done cautiously. Further studies are needed to determine the effect of high-dose nicotinamide on in vivo carcinogenesis and genomic stability of the cancer cells and the surrounding normal cells.

References:

Devita Surjana, Gary M. Halliday, and Diona L. Damian, “Role of Nicotinamide in DNA Damage, Mutagenesis, and DNA Repair,” Journal of Nucleic Acids, vol. 2010, Article ID 157591, 13 pages, 2010. doi:10.4061/2010/15

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