Stephen S. Hecht, Principal Investigator

Biochemistry, Biology, and Carcinogenicity of
Tobacco-Specific N-Nitrosamines

  Cigarette smoking causes approximately 30% of all cancer death in the U.S. It is responsible for 85% of the 160,000 lung cancer deaths expected in 2001. In spite of advances in tobacco control and smoking cessation, there are still 48 million smokers in the U.S., and about 25% of the adult population. Approximately 500 billion cigarettes and 121 million pounds of smokeless tobacco were consumed in 1997 in the U.S. Tobacco-specific N-nitrosamines are formed from tobacco alkaloids during the curing and processing of tobacco products. Seven tobacco-specific N-nitrosamines have been identified in tobacco products. Two of these, 4-(methylnitro-samino)-1-(3-pyridyl)-1-butanone (NNK) and N-nitrosonornicotine (NNN), are present in substantial quantities and are strong carcinogens. NNK is a potent pulmonary carcinogen in rodents and also induces tumors of the pancreas, nasal mucosa, and liver. NNN causes tumors of the esophagus and nasal mucosa in rats and respiratory tract tumors in mice and hamsters. A mixture of NNK and NNN induces oral tumors in rats.

  Based on their carcinogenic activities, the extensive data on the occurence of NNK and NNN in tobacco products, and on biochemical studies, these researchers hypothesized that such compounds play a significant role as causative factors in human cancers associated with tobacco use.

  Specific aims of this research were to investigate:

1. stereoselectivity in the metabolism of NNK and NNN by delineating differences in the formation and further metabolism of enantiomers of the major NNK metabolite NNAL, determining differences in the stereoselectivity of metabolic activation of NNK, and examining differences in the metabolic activation and carcinogenicity of NNN enantiomers;

2. DNA and protein pyridyloxo-butylation by NNK and NNN by elucidating the structures of the major adducts formed with DNA and hemoglobin; and

3. the metabolism of NNK and NNN in humans by determining levels of NNN metabolites in human urine, characterizing previously unknown NNN metabolites, and examining NNK metabolites in the urine of snuff-dippers to determine their persistence after cessation and their amounts as a function of dose.

The overall theme of this work was based on mechanistic studies of NNK and NNN metabolism and adduct formation, in order to further evaluate the carcinogenic potential of NNK and NNN in humans exposed to tobacco products.