N-Nitrosamine Research Paper

The carcinogenic nature of N-nitrosamines depends on the organs. For example, their targets for cancer in rodents include thyroid, pancreas, urinary bladder, trachea, lung, oral and nasal cavities, esophagus, kidney and liver. With respect to N-nitrosamides, skin, bone, peripheral nervous system, brain, small intestine and glandular stomach are targeted organs for cancers. Besides cancer, acute myelocytic leukemia and T and B cell lymphoma have also been triggered by N-nitrosamides. In table 8.1, some N-nitrosamines and their main targets organs are summarized. Another property of the carcinogenicity of N-nitrosamines is that a single dose in large amount is less effective than multiple doses in small amount (Pegg & Shahidi 2000). The carcinogenesis of N-nitrosamines requires several steps shown in figure 1. As N-nitrosamines are biochemically stable, they firstly need to be activated to form alpha-hydroxynitrosamines. This is done by cytochrome P450-dependent
hydroxylation at the carbon next to the N-nitroso group. The second step involves an elimination reaction which leads to the formation of alkydiazohydroxides. This spontaneous reaction involves the elimination of an aldehyde through breaking the C-N bond. Unlike N-nitrosamines, N-nitrosamides are biochemically active under favorable pH conditions. For example, as shown in the figure, alkylnitrosourea is active under pH 7.4. When these N-nitrosamides break down, alkyldiazohydroxides are also formed. The alkyldiazohydroxides formed are then converted to diazonium ions, which are electrophilic and carcinogenic. These ions are able to react with multiple cellular components at their nucleophilic sites including DNA. DNA alkylation is a typical pathway to induce cancer. It starts off by generating a series of modified bases. For example, a study has evaluated the profile of the modified bases formed by NMDA activation in the rat liver. They concluded that the site of alkylation is related to both the alkylating agent and the tissue type. More studies have been conducted and have found that the metabolic activity of N-nitrosamines in the organs of humans and animals are comparable. For example, according to a study conducted by Montesano and Magee, livers of humans as well as of monkeys, trout and Syrian golden hamsters all showed metabolic activity for NDMA. Among them, the metabolic activity of human liver is most similar to that of rat liver. Studies nowadays have shown that all human organs can metabolize simple symmetrical diakylnitrosamines while some organs cannot metabolize asymmetrical and cyclic diakylnitrosamines. Besides, metabolic rates vary greatly among individuals (Tricker & Preussmann 1990).
The modified bases are not equally carcinogenic. For example, the most prevalent modified base in DNA formed by alkylating the 7th position of guanine does not induce cancer. Furthermore, modified bases can be repaired by apyrimidation, enzyme apurination as well as hydrolysis. However, once being persistent, O6-alkylguanine and O4-alkylthymine residues cause mispairing of bases during polyribonucleotide or polydeoxyribonucleotide production. In rats, O6-alkylguanine caused tumors in mammary glands by miscoding with thymine during DNA replication. This is a single point mutation (G.C-A.T transition) and it leads to the formation of N-nitrosomethylurea (NMU), a carcinogen in rats. A large fraction of tumors brought by NMU comprise Ha-ras oncogenes which are activated by G-A transitions at the 12th codon (Tricker & Preussmann 1990).
What links rats and humans is that ras oncogenes were also activated (especially at the 12th codon) in a number of human tumors. For example, K-ras gene was activated by G-A transitions at the 12th codon in human colon adenomas and carcinomas. This activation is associated with the incorporation of alkylating agents including N-nitroso compounds. Furthermore, K-ras gene was activated by G-T tranversions at the 12th codon in acinar carcinomas of the pancreas and lung tumors (Tricker & Preussmann 1990).
The study of carcinogenesis of N-nitrosamines is very complex since a number of parameters come into play including differences in activation capacities between enzymes present in different tissues and differences in repair capacities for modified bases in different organs or in different cells within an organ.
Moreover, carcinogenesis of N-nitrosamines differs from that of N-nitrosamides in that N-nitrosamides induce regional and systemic tumors whereas N-nitrosamines only induce systemic tumors which occur far away from the place of application (Tricker & Preussmann 1990).
However, according to DNA studies, tumors were found only in some organs where methylated DNA was recognized. This indicates that cancerous cells cannot be initiated by DNA alkylation alone. The primary factor that comes into play has been suggested as the role of cyclic nitrosamines since cyclic nitrosamines are structurally hindered to induce DNA alkylation, but have also exhibited carcinogenicity (Tricker & Preussmann
1990).