We study the metabolism of nicotine, nitrosamines and other tobacco-related carcinogens. Nicotine is not a carcinogen, but nitrosamines are potent carcinogens and are believed to be causative agents for a number of human cancers. We are particularly interested in the tobacco specific nitrosamine, NNK. NNK requires cytochrome P450-catalyzed metabolism to exert its carcinogenic potential. Two P450 2A enzymes catalyze NNK bioactivation with strikingly different efficiencies. Interestingly, the more efficient of these, P450 2A13 is expressed in the human lung and NNK is a lung carcinogen. In addition to characterizing the role of P450s in carcinogen metabolism, we are interested in the role of UDP-glucuronosyl transferases (UGTs) and glutathione S-transferases (GSTs) in the detoxification of some of these compounds. To study metabolism and carcinogen exposure in smokers we use (and develop) sensitive LC-MS/MS methods to quantify nicotine and carcinogen metabolites in various biological matrices.
At similar smoking levels, the lung cancer risk varies more than 4-fold across different ethnic groups. We have investigated the role of UGT and P450 variants in nicotine and carcinogen metabolism in this variable cancer risk. These studies are part of a multi-institutional collaborative effort with epidemiologists and geneticists. The hypothesis driving this research is that differences in the activation and detoxification of tobacco constituents contribute significantly to the variable lung cancer risk of smokers.
