Genotoxicity Study on Nicotine and Nicotine-Derived Nitrosamine by Accelerator Mass Spectrometry

Abstract

We have studied DNA adduction with 14C-labe1ed nicotine and nicotine-derived nitrosamine, 4-(methylnitrosamino)1-(3-pyridyl)-1-butanone (NNK), by accelerator mass spectrometry (AMS) in mouse liver at doses equivalent to lowlevel exposure of humans. The dose ranges of nicotine and NNK administered were from 0.4g to 4.0x 10^2 micrograms kg b.w.-1, and from 0.1 micrograms to 2.0x10^4 micrograms kg b.w.-1, respectively. In the exposure of mice to either nicotine or NNK, the number of DNA adducts increased linearly with increasing dose. The detection limit of DNA adducts was 1 adduct per 1011 nucleotide molecules. This limit is 1-4 orders of magnitude lower than that of other techniques used for quantification of DNA adducts. The results of our animal experiments enabled us to speculate that nicotine is a potential carcinogen. According to the procedure for 14C-labeled-NNK synthesis, we discuss the ultimate chemical speciation of NNK bound to DNA. From the animal tests we derived a directly perceivable relation between tobacco consumption and DNA adduction as the carcinogenic risk assessment.