My laboratory studies the activation and detoxification pathways of nicotine and carcinogens; investigating the role of these pathways in tobacco carcinogenesis. We use LC-MS/MS based methods to quantify nicotine and carcinogen exposure and metabolism in people. In collaborations with geneticists and epidemiologists, we study the contribution of enzyme variants and individual differences in metabolism to lung cancer risk.
We study the metabolism of nicotine and nitrosamines. 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 NNK metabolism, we are determining the role of UDP-glucuronosyl transferases (UGTs) in the detoxification of this lung carcinogen.
A second goal of my laboratory is to characterize the enzymes involved in nicotine metabolism. We are investigating the specificity and selectivity of particular P450s and UGTs for nicotine metabolism. We discovered that P450 2A6 and P450 2A13 are inactivated during nicotine metabolism; a metabolite of nicotine reacts with the enzyme and irreversible inhibits further catalysis. More recent studies have suggested that a secondary metabolite of nicotine β-nicotyrine may be the metabolite responsible for inactivation of P450 2A6. On-going studies will characterize the mechanism of this inactivation.
At similar smoking levels, the lung cancer risk varies more than 4-fold across different ethnic groups. A third project in the lab investigates the role of UGT and P450 variants in nicotine and NNK metabolism in this variable cancer risk. These studies, as part of a multi-institutional collaborative effort, are being carried out in the context of a whole genome wide association study of tobacco induced lung cancer. The hypothesis being that differences in the activation and detoxification of tobacco constituents contributes significantly to the variable lung cancer risk of smokers.