Nitrosamines (Molecular Biology)

Nitrosamines (#-nitrosoamines), typified by #-nitrosodimethylamine and #-nitrosodiethanolamine (Fig. 1), are mutagens and are reactive compounds that readily alkylate DNA via an reaction (slow formation of an alkylcarbenium ion and rapid reaction of this with nitrogen, oxygen, and phosphorus atoms on DNA). N-Nitrosoamines are widespread in the environment and can be formed endogenously in humans (1-3). For example, workers in the rubber industry are exposed to high levels of N-nitrosodiethanolamine, which is a potent carcinogen over a considerable dose range and in more than one species. A wide range of volatile N-nitrosoamines are found in fried bacon and other pork products, while a different range of N-nitrosoamines are present in tobacco products and believed to play a significant role in human cancers associated with tobacco use. N-Nitrosoamines are potent carcinogens in every animal species tested; and although their role in human cancer is not definitively proved, it is considered highly likely that they are human carcinogens (2, 4).

Figure 1. Structures of the nitrosamines N-nitrosodimethylamine and N-nitrosodiethanolamine.

Structures of the nitrosamines N-nitrosodimethylamine and N-nitrosodiethanolamine.


One of the most extensively studied compounds in this class is N-nitrosodimethylamine (NDMA). This chemical is nonreactive per se, but can be metabolized to an S^-type methylating agent, primarily by cytochrome P450 IIE1. Although the metabolite reacts primarily to form around 60% Ny-methylguanine DNA adducts, it also generates a significant amount (approximately 6%) of O6- methylguanine, as well as other minor N- and O-alkylated bases. ^-Methylguanine and other O- alkylated adducts are directly miscoding, and they introduce base pair substitutions upon DNA replication; extensive evidence exists to link these lesions with mutagenesis and carcinogenesis by NDMA and related agents. NDMA has been described as the most powerful methylating agent known (5).

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