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

Stephen S. Hecht, Ruth Young

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17 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1195-1199
Number of pages5
Issue number10
StatePublished - 1982

Bibliographical note

Funding Information:
This study was supported by NCI Grants CA-21393 and CA-29580. We thank Ms. Amy Juchatz for her outstanding assistance with the short term culture of rat esophagus. High resolution mass spectra were kindly provided by Dr. James McCloskey, University of Utah. We thank Dr. Conway Chang, Columbia University, for 250 MHz n.m.r. spectra.


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