Evidence for endogenous formation of N′-nitrosonornicotine in some long-term nicotine patch users

Abstract

Nitrosation of nicotine or its metabolites in the human body could lead to formation of the 2 carcinogenic tobacco-specific nitrosamines—N′-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). We investigated the possibility of endogenous formation of NNN in people who had stopped smoking and used the 21-mg nicotine patch for 6 months. We quantified urinary biomarkers of exposure to NNN—the sum of NNN and its pyridine-N-glucuronide, referred to as total NNN. Also measured were NNK metabolites—the sum of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its N- and O-glucuronides, referred to as total NNAL. The average decline of urinary total NNN was less drastic than that of total NNAL: 22% of baseline total NNN and 7.3% of baseline total NNAL were detected in urine 24 weeks after smoking cessation and patch use (p = .02). The average ratio of total NNN to total NNAL in the same urine samples increased from 0.14 in baseline urine to 0.38 after 24 weeks of nicotine patch use. Overall, these results demonstrate that endogenous formation of NNN may occur in nicotine patch users. However, the levels of urinary total NNN during patch use were generally extremely low. Moreover, in 10 of 20 subjects analyzed here, the rate of decline in total NNN was similar to that in total NNAL, indicating that endogenous formation of NNN is virtually nonexistent in these subjects. Supplementation with ascorbic acid could be a simple approach to block possible NNN formation in nicotine patch users.