N-nitroso compounds and human cancer: where do we stand?

Humans are exposed not only to preformed N-nitroso compounds (NOC) but also to a wide range of nitrogen-containing compounds and nitrosating agents which can react in vivo to form NOC, a versatile class of carcinogens. Nitrosating agents and NOC can also be synthesized endogenously in reactions mediated by bacteria and activated macrophages. Thus, endogenous formation of NOC can occur at various sites in the body. A sensitive procedure (the N-nitrosoproline (NPRO) test) has been developed to estimate exposure of humans to exogenous and endogenous NOC. Results of studies in human subjects with this test led to the following conclusions: (1) The process of endogenous nitrosation in humans is influenced by many factors; therefore, determination only of nitrate and nitrite in body fluids is insufficient to assess the extent of nitrosation in man in vivo. (2) In clinical studies to examine the model of gastric carcinogenesis based on bacterial colonization and nitrosation in vivo, progress has been made in explaining some steps, but several controversies remain. Although bacterial strains possessing enzymes that catalyse N-nitrosamine formation at neutrality have been isolated from the gastric juice of achlorhydric subjects, their precise role in gastric carcinogenesis remains to be clarified. (3) Formation of endogenous NOC was assessed by the NPRO test in: (i) subjects living in high- and low-incidence areas for stomach cancer in northern Japan, Costa Rica and Poland; (ii) subjects with different habits of betel-quid chewing and tobacco use; (iii) patients with urinary bladder infections; and (iv) subjects infested with liver fluke in Thailand. In all instances, greater exposure to endogenous NOC was found in high-risk subjects, but individual exposure was greatly affected by dietary modifiers of disease state: ascorbic acid efficiently lowered the body burden of intragastrically formed NOC. (4) Increased nitrosation is also observed in tobacco smokers, adding to the body burden of ingested or inhaled tobacco-related carcinogens. These results, together with the knowledge that NOC produce tumours in 40 animal species, clearly underline the potential role of NOC (and other nitrite-reactive compounds) in human cancer etiology, particularly when exposure starts early in life and persists over a long period. The demonstrated efficacy of certain vitamins as nitrosation inhibitors also provides a plausible interpretation of epidemiological findings that have shown protective effects of fruits and vegetables (sources of vitamins and polyphenols) against various malignancies and particularly stomach cancer.(ABSTRACT TRUNCATED AT 400 WORDS)