Secondary Targets of Nitrite-Derived Reactive Nitrogen Species: Nitrosation/Nitration Pathways, Antioxidant Defense Mechanisms and Toxicological Implications

A review. Nitrite, the primary metabolite of nitric oxide (NO) and a widely diffused component of human diet, plays distinct and increasingly appreciated roles in human physiol. However, when exposed to acidic environments, typically in the stomach, or under oxidative stress conditions, it may be converted to a range of reactive nitrogen species (RNS) which in turn can target a variety of biomols. Typical consequences of toxicol. relevance include protein modification, DNA base deamination and the formation of N-nitrosamines, among the most potent mutagenic and carcinogenic compds. for humans. Besides primary biomols., nitrite can cause structural modifications to a variety of endogenous and exogenous org. compds., ranging from polyunsatd. fatty acids to estrogens, tocopherol, catecholamines, furans, retinoids, dietary phenols, and a range of xenobiotics. The study of the interactions between nitrite and key food components, including phenolic antioxidants, has therefore emerged as an area of great promise for delineating innovative strategies in cancer chemoprevention. Depending on substrates and conditions, diverse reaction pathways may compete to det. product features and distribution patterns. These include nitrosation and nitration but also oxidn., via electron transfer to nitrosonium ion or nitrogen dioxide. This contribution aims to provide an overview of the main classes of compds. that can be targeted by nitrite and to discuss at chem. levels the possible reaction mechanisms under conditions that model those occurring in the stomach. The toxicol. implications of the nitrite-modified mols. are finally addressed, and a rational chem. approach to the design of potent antinitrosing agents is illustrated.