MERIT Award Recipient: Stephen S. Hecht, Ph.D.
Metabolism of Carcinogenic Tobacco-Specific Nitrosamines
Cigarette smoking causes 30% of all cancer death in developed countries. According to a recent evaluation by the International Agency for Research on Cancer, the following cancers are caused at least in part by smoking: lung, oral cavity, naso-, oro- and hypopharynx, nasal cavity and paranasal sinuses, larynx, esophagus, stomach, pancreas, liver, kidney, ureter, urinary bladder, uterine cervix, and myeloid leukemia. Secondhand smoke causes lung cancer in non-smokers. "Smokeless" tobacco products such as snuff and betel quids are important causes of oral cancer. The overall goal of research in the Hecht laboratory is to understand the mechanisms by which carcinogens (cancer causing agents) in tobacco products cause cancer in humans, and to use this information to develop practical approaches to cancer prevention.
One of the most important groups of carcinogens in tobacco and tobacco smoke is the tobacco-specific nitrosamines. These carcinogens are formed from nicotine and related compounds by a nitrosation reaction that occurs during the curing and processing of tobacco. They are called tobacco-specific nitrosamines because they are found only in tobacco products (and possibly in some other nicotine-containing products). Thus the tobacco-specific nitrosamines are present in both "smokeless" tobacco products such as oral snuff and in cigarette smoke. They are the most prevalent strong carcinogens in "smokeless" tobacco products, occurring at much higher levels than in any other marketed product designed for oral use. They are among the most important carcinogens in cigarette smoke, along with combustion products and other carcinogens.
Among the tobacco-specific nitrosamines, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) are the most carcinogenic. NNK and its metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) are potent systemic lung carcinogens in rats. Tumors of the nasal cavity, liver, and pancreas are also observed in NNK- or NNAL-treated rats. NNN is an effective esophageal carcinogen in the rat, and induces respiratory tract tumors in mice, hamsters, and mink. A mixture of NNK and NNN caused oral tumors when swabbed in the rat oral cavity. Thus, considerable evidence supports the role of tobacco-specific nitrosamines as important causative factors for cancers of the lung, pancreas, esophagus, and oral cavity in people who use tobacco products.
Metabolism and chemical binding to DNA (adduct formation) are critical in cancer induction by NNK and NNN. The goal is to better understand these processes. In this project, the Hecht laboratory will use mass spectrometry and related analytical biochemistry approaches to fully characterize the complex array of DNA adducts that is formed from NNK and NNN in treated rodents as well as in humans. They will also determine the extent to which NNK and NNN may be formed from nicotine in humans and the balance between metabolism to harmless excreted products (detoxification) and to products which form DNA adducts. Other studies will focus on long-term biomarkers of human uptake of tobacco-specific nitrosamines. Human metabolism of NNK and NNN varies widely from individual to individual, and the ultimate goal of this research is to identify those individuals who are particularly sensitive to the carcinogenic effects of these compounds. Such individuals would be at higher risk for cancer when they use tobacco products or are exposed to secondhand smoke. Identification of high-risk individuals could lead to improved methods of prevention of tobacco-related cancer.