METABOLISM OF N'-NITROSONORNICOTINE BY ADULT AND FETAL HUMAN OESOPHAGAL CULTURES

The metabolism of [H-3]labelled N-Nitrosonornicotine a major constitue nt of the class of Tobacco Specific Nitrosamines was studied in adult and fetal human oesophageal cultures. The metabolites were separated b y HPLC and were identified when compared to the standards as OH-acid f rom 5'hydroxylation, NNN-1-N-oxide formed via the pyridine N-oxidation pathway and Keto acid from 2'hydroxylation in both the adult and feta l cultures. These results' indicate that hydroxylation which leads to electrophilic diazohyroxides is the major pathway of NNN metabolism in cultured human oesophagus. In the adult cultures levels of metabolite s formed were 20.32 pmoles/mu g DNA of OH acid 11.08pmoles/mu g DNA of NNN-1-N-oxide and 7.67pmoles/mu g DNA of Keto acid. In the fetal cult ures levels were 10.85pmoles/mu g DNA of OH acid, 9.40pmoles/mu g DNA of NNN-1-N-oxide and 7.9lpmoles/mu g DNA of Keto acid. These results i ndicate that alpha-hydroxylation is the key step in the metabolic acti vation of NNN in human oesophagus.