Blocking the endogenous formation of N-nitroso compounds and related carcinogens

Humans are exposed to a wide range of nitrogen-containing compounds and nitrosating agents, such as nitrite, nitrate and nitrogen oxides (NOx), that can react in vivo to form potentially carcinogenic N-nitroso compounds (NOCs), as well as several carcinogenic C-nitro(so) or reactive diazo compounds. Nitrosating agents can also be synthesized endogenously by bacteria and activated macrophages via the nitric oxide (NO) synthase pathway. Endogenous nitrosation can thus occur at many locations in the body, including sites of chronic infection or inflammation. Ascorbic acid, alpha-tocopherol, phenolic compounds, and fruit, vegetable and plant extracts inhibit NOC formation by destroying nitrosating agents. Fresh fruits and vegetables (sources of nitrosation inhibitors) exert a protective effect against various epithelial cancers. In addition to giving rise to nitrosating agents, overproduction of NO in chronic inflammatory conditions leads to the generation of peroxynitrite (a source of oxidative DNA damage and lipid peroxidation) and aldehydes and epoxides derived from lipid peroxidation that yield miscoding exocyclic DNA adducts. Inhibition of the inducible NO synthase and strengthening of the cellular defence system against oxidative stress should block NO-associated DNA damage. This chapter summarizes mechanistic, experimental and human studies that address the inhibition of endogenous formation of NOCs and related carcinogens as a method of chemoprevention.