Effects of nicotine infusion on the metabolism of the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in rats

The tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a lung carcinogen in the rat and believed to be a causative agent for lung cancer in smokers. To exert its carcinogenic potential NNK is metabolically activated by cytochrome P450-catalyzed α-hydroxylation. Nicotine and NNK share metabolic pathways. The purpose of this study was to determine whether nicotine alters the fraction of NNK undergoing activation to carcinogenic metabolites. Rats received acute (36 h) or chronic (2 week) s.c. infusions of nicotine at rates producing serum nicotine concentrations 2–3 times the usual venous nicotine concentrations measured in smokers. A single dose of [5-3H]-NNK was administered i.p. 24 h prior to the end of each infusion. Urine was collected for 24 h thereafter and NNK metabolites quantified by radioflow HPLC. Neither acute nor chronic nicotine infusion had any effect on the extent of NNK metabolism by α-hydroxylation. These data suggest that nicotine infusion, at rates simulating the higher doses of nicotine replacement therapy now being studied for smoking cessation, neither induces nor inhibits NNK metabolism appreciably and therefore should not alter the formation of carcinogenic NNK metabolites.