title: Regiospecificity in the metabolism of the homologous cyclic nitrosamines, N'-nitrosonornicotine and N'-nitrosoanabasine.
abstract: 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-nitrosopiperidine). 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 alpha-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.
mesh_terms: D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism*; D004938:Esophageal Neoplasms / Q000139:chemically induced; D004947:Esophagus / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D009374:Neoplasms, Experimental / Q000139:chemically induced; D009602:Nitrosamines / Q000378:metabolism*; D009924:Organ Culture Techniques; D051381:Rats; D011916:Rats, Inbred F344; D013329:Structure-Activity Relationship
chemical_list: D002273:Carcinogens; D009602:Nitrosamines; C010257:N'-nitrosoanabasine; C008655:N'-nitrosonornicotine