A Study of Tobacco Carcinogenesis. XIV. ERects of N '-Nitrosonornicotine and N '-Nitrosonanabasine in Rats 2

Abstract

N'-Nitrosonornicotine (NNN) and N'-nitrosoanabasine (NAB) were synthesized and administered in drinking water to male Fischer rats for 30 weeks (total dose, 630 mg). 1,4-Dinitrosopiperazine (DNPI) served as the positive control. By 11 months, all surviving rats given NNN developed esophageal tumors (12/20); 1 had a pharyngeal tumor and 3 had invasive carcinomas originating in the nasal cavity. During the same time, only 1 of 20 rats given NAB developed esophageal tumors. Compared to the strong esophageal carcinogen DNPI, NNN was a moderately active and NAB a weak carcinogen. NNN (0.3-90 parts per million) in chewing tobacco was related to the observation that cancer of the oral cavity and esophagus in man was correlated with the chewing of tobacco.

Structure-activity relations in carcinogenesis by N-nitroso compounds

“…A pyridyl derivative of nitrosopyrrolidine is nitrosonornicotinc (55c), a major carcinogen in tobacco and tobacco smoke [65]. It is somewhat weaker than 55 and induces tumors of the nasal mucosa [122] and of the esophagus [123], but not of the liver or lung in rats. The low activity might be a consequence of the basicity of the pyridinc ring.…”

“…The low activity might be a consequence of the basicity of the pyridinc ring. Analogous to 55c is nitrosoanabasine (56q), also a constituent of tobacco smoke, which is a much weaker carcinogcn than nitrosopiperidine and induces some tumors of thc esophagus in rats [123]. Nitrosoanatabine, the analogous pyridyl derivative of 56x, is inactive.…”

Tobacco specific nitrosamines: Carcinogenicity, metabolism, and possible role in human cancer

“…A low level of non-extractable radioactivity was observed in the liver. These results suggest that the esophageal mucosa of both strains has the ability to activate NNN to reactive species, although the F344 rats are more susceptible to develop esophageal papillomas (15,16).…”

“…Subcutaneous injection of NNN in either saline or trioctanoin does not induce esophageal tumors, but rather causes nasal cavity tumors (13)(14)(15).…”

“…In F344 rats, equimolar doses of NNN and NNK induced a high percentage of nasal cavity tumors but only NNK caused a high incidence of lung and liver tumors (13). Comparative assays of NNN and NA3 in both F344 rats and Syrian golden hamsters clearly showed that the former was more potent (15,17). A comparative study of NNN, NNK, and NNA in A/J mice demonstrated that NNA was inactive (11).…”