Environmental Chemical Skin Carcinogenesis Concerning the Development of Melanoma and Keratinocyte Cancer: From Nitrosocontamination / Endogenous Nitrosation in Pharmaceuticals to Photocarcinogenicity in Humans

Nitrosamines have been recognized since the 1930s as carcinogens, and as photolabile compounds capable of undergoing photodegradation, regardless of their carcinogenic potential. While larger studies are gradually being conducted and officially acknowledged, single case reports often provide highly valuable clinical insights, reflecting real-world clinicopathological correlations. Drugs such as those taken by the patient presented (like ramipril/amlodipine, moxonidine, febuxostat, esomeprazole) share several important characteristics: All five have been discussed in the literature in the context of potential 1) nitrosamine contamination or 2) formation from secondary/tertiary amines under specific (acidic) conditions. For each of them, literature data from recent decades suggest the possibility of systemic distribution with accumulation in peripheral tissues, including the skin. It should be noted that the FDA’s Daily acceptable intake (AI) limits for nitrosamines are largely derived from mutagenicity and carcinogenicity data, including bacterial assays such as the Ames test (using Salmonella typhimurium and/or Escherichia coli strains). However, while these assays are well established for detecting mutagenic potential, they cannot replicate the complexity of the so called dynamic human skin related carcinogenesis. In particular, they may not adequately account for mechanisms such as Nitroso phototoxicity/ Nitroso photocarcinogenicity, were photochemical reactions in peripheral tissues - such as the skin - could occur independently of, or prior to, hepatic metabolic activation of the drugs mentioned. Consequently, localized ultraviolet-driven chemical reactions and/or independent tissue-specific oxidative or nitrosative stress pathways may not be sufficiently reflected in standard bacterial-based risk models. Already published national and international data, suggest a pathogenetic association between polymedication intake and the increased skin cancer risk, particularly in chronically treated, polymorbid patients.In clinical practice, these considerations raise the possibility that photocarcinogenicity - and more specifically, Nitroso Photocarcinogenicity - may be influenced by the combined effects of polymedication, especially in the presence of potential nitrosamine contamination/ endogenous formation (even without contamination).These processes also depend on individual pharmacokinetic and pharmacodynamic profiles of each drug, as well as on individual variability in metabolism, enzyme activity, and tissue distribution. Nitroso mediated Photocarcinogenesis may additionally be influenced by nutritional Nitrosogenesis: nitrosamines may be introduced into the body through medication without any availability of external Nitrosamine contamination. If the drugs posses secondary or tertiary amino group, there is a possibility to undergo on that way the so called endogenous Nitrosation/ Nitrosamine formation in the presence of nitrites rich food intake in acidic environment (in the stomach) - leading to the in vivo formation of N-nitrosamines. Polymedication (ramipiril/amlodipine, moxonidine, febuxostat, esomeprazole) and the subsequent development of cutaneous melanoma and BCC skin tumors located in close proximity, can once again be explained within the conceptual framework of the so called exogenous Nitrosocontamination and the endogenous drug related Nitrosogenesis leading subsequently to the drug related Nitroso- Photocarcinogenesis.