Metabolism of tobacco-specific N-nitrosamines by cultured human tissues.

Abstract

N''-Nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are present in cigarette smoke and snuff and are carcinogens in laboratory animals. In tobacco smokers, the buccal mucosa, trachea, esophagus, bronchi and peripheral lung cancer are exposed to smoke containing significant amounts of these N-nitrosamines. Explants of these tissues as well as of the urinary bladder have the capacity to metabolize NNN and NNK by .alpha.-carbon hydroxylation. This metabolic pathway yields alkyldiazohydroxides, which are reactive and DNA-damaging electrophiles. The extent of .alpha.-carbon hydroxylation of NNN and NNK in human tissues was only 1/10-1/100 of that in animal tissues. Although the levels of .alpha.-carbon hydroxylation of NNN among different tissues of the same individual were similar, a 10-fold variation among individuals was observed. Reduction of the NNK carbonyl group was a major metabolic pathway observed with all human explants and may occur in the surface epithelia of the respiratory tract of smokers. Tobacco-specific N-nitrosamines could play a role in cancers related to the smoking and chewing of tobacco.