DNA damage induced by reactive nitrogen species

Abstract

Chronic infection by bacteria, parasites or viruses and tissue inflammation such as gastritis and colitis are recognized risk factors for human cancers at various sites. Reactive oxygen and nitrogen species produced by activated inflammatory cells play an important role in the multistage carcinogenesis process, by inducing DNA and tissue damage and mutations. Nitric oxide (NO), generated enzymatically from L-arginine by constitutive and inducible NO synthases, acts not only as a signal molecule mediating various physiological functions, such as vasodilation and neurotransmission, but also acts as a mediator of the cytotoxic activity of macrophages, playing an important role in inflammation processes. Excess NO in the presence of oxygen can be converted to nitrosating agents, which can damage DNA through various mechanisms including deamination, induction of strand breaks and alkylation by nitrosamines formed by reaction of secondary amines with nitrosating agent(s) derived from NO. Superoxide also reacts rapidly with NO to yield a potent oxidant, peroxynitrite, which can induce DNA strand breaks and causes various DNA base modifications through nitration, oxidation and deamination. On the other hand, NO has been shown to protect against DNA damage or lipid peroxidation mediated by the Fenton-type reactions (H2O2 plus metal ions). In these cases NO may form a complex with a metal ion and/or reactive species or terminate chain reaction of lipid peroxydation, inhibiting formation of reactive species. The balance between production of NO and reactive oxygen species and interactions of NO with metal ions are important in inflammation-associated human diseases including cancer.