A fine line between therapeutic benefits and potential risks characterizes using niacinamide in dermatology. In small and moderate doses, niacinamide has a positive effect on the skin, improving its barrier function and reducing inflammation. However, as the dosage is increased, questions about its safety arise. For example, it has been shown that at concentrations above 20 mM, niacinamide can induce apoptosis of skin cells [1]. Although scientists later attributed the lethality of such high doses of niacinamide to the osmotic shock of the cell in a hypertonic solution rather than biochemical effects, the tolerability of high doses is still a matter of debate.

In the context of oncology and genotoxicity, the effect of nicotinamide on the genetic apparatus of the cell is of particular interest. One of the "levers" of this effect is poly-(ADP-ribose)-polymerase (PARP), a family of proteins involved in several cellular processes, such as DNA repair, genome stability, and programmed cell death. On the one hand, it has been found that niacinamide and other poly-(ADP-ribose)-polymerase (PARP) inhibitors can increase chromatid exchange and cause structural abnormalities of chromosomes. On the other hand, niacinamide deficiency enhances the potential of PARP inhibitors to damage chromatids, which may indicate a protective effect of niacinamide [2].

Studies showing different effects of niacinamide depending on the organ and stage of tumor development are interesting. In some experiments, niacinamide promoted the development of tumors in some organs but reduced their development in other organs, indicating the organ-specificity of its effect [2].

Niacinamide also affects cell metabolism. For example, in experiments on human fibroblasts, it was shown that treatment with niacinamide can lead to a 10% decrease in adenosine triphosphate (ATP) levels [2]. This indicates a potential effect of niacinamide on cellular energy balance, which may have long-term implications for cellular function and skin health.

The effect on protein synthesis is an essential aspect in studies of high concentrations of niacinamide and their influence on cell biosynthetic processes. It has been shown that an increase in the level of NAD+ in cells can reduce the efficiency of protein translation, potentially disturbing the overall protein balance [3], leading to various pathological conditions, including some forms of cancer. This discovery is particularly significant in dermatology, as the protein balance of skin cells directly affects skin health and appearance. Disruption of protein synthesis can lead to impaired elasticity and regenerative capacity of the skin, enhancing the aging process and the development of skin diseases.

Niacinamide is essential in regulating DNA methylation, which is important for gene expression. Disturbances in this process can have serious consequences, including the risk of developing metabolic disorders such as obesity and type 2 diabetes. The link between high doses of niacinamide and the development of insulin resistance has been the subject of much attention in the medical community. Clinical studies in humans and animals indicate a potential risk of decreased insulin sensitivity with long-term administration of high doses of niacinamide. This fact is particularly relevant given the increasing prevalence of metabolic syndrome and related diseases such as type 2 diabetes.

Numerous studies emphasize the need for cautious use of niacinamide in high doses, given the data on its potential genotoxicity, effects on energy metabolism, protein synthesis, and the risk of insulin resistance and metabolic syndrome.

References

1. Li D., Tian Y.J., Guo J. al. Nicotinamide supplementation induces detrimental metabolic and epigenetic changes in developing rats. Br J Nutr 2013; 110: 2156–2164.
2. Kang H.T., Lee H.I., Hwang E.S. Nicotinamide extends replicative lifespan of human cells. Aging Cell 2006; 5: 423–436.
3. Hwang E.S., Song S.B. Possible Adverse Effects of High-Dose Nicotinamide: Mechanisms and Safety Assessment. Biomolecules 2020; 10: 687.