Regiospecificity in the metabolism of the homologous cyclic nitrosamines, N' -nitrosonornicotine and n' -nitrosoanabasine

We compared the metabolism in the F-344 rat of the moderately potent esophageal carcinogen N' -nitrosonornicotine (NNN, 2' -(3-pyridyl)-N-nitrosopyrrolidine) and its weakly active homologue N'-nitrosoanabasine (NAB, 2' -(3-pyridyl)-N-nitrosopiperldine). Urine was the major pathway of excretion for both nitrosamines. The major urinary metabolites of dl-NNN resulted from 2' -hydroxylation (8.1% of the dose), 5' -hydroxylation (37.6%), and pyridine N-oxidation (10.8%). The percentages of the dose of the corresponding metabolites of dl-NAB were: 2'-hydroxylation (not detected), 6'-hydroxylation (9.8%), pyridine-N-oxidation (30.0%). Similar results were obtained when the urinary metabolites of l-NNN and l-NAB were compared. In 48 h cultures of rat esophagus, the major metabolites of [2' -¹⁴C]dl-NNN resulted from 2' -hydroxylation (47%) and to a lesser extent from 5'-hydroxylation (15%). In contrast the major metabolite of [2'-¹⁴C]dl-NAB resulted from 6'-hydroxylation (35%) with lesser amounts from 2'-hydroxylation (8%). 6'-Hydroxylation of [2'-¹⁴C]dl-NAB also exceeded 2' -hydroxylation in cultures of 3,6,12 or 24 h duration. Pyridine-N-oxidation was not observed in the esophagus for either nitrosamine. These results demonstrate a high degree of regiospecificity in the metabolism of these structurally related nitrosamines. Among the identified urinary metabolites the ratio of α-hydroxylation to N-oxidation was 4.2 for NNN and 0.3 for NAB. Among the 48 h esophageal metabolites the ratio of 2'-hydroxylation to 5' - or 6' -hydroxylation was 3.1 for NNN and 0.2 for NAB. The results also suggest a basis for the weak carcinogenicity of NAB: facile excretion as its pyridine-N-oxide and detoxification in the esophagus by 6' -hydroxylation.