The influence of nicotinic hepatic metabolism on neuroreceptor substrates of nicotine addiction

We will examine differences in nAChR availability based on individual differences in the nicotine metabolism rate. Work conducted by Dr. Lermans group at Penn, in collaboration with Drs. Rachel Tyndale (University of Toronto) and Neal Benowitz (University of California, San Francisco) has documented differences in smoking cessation and treatment response between slow and normal metabolizers of nicotine. Nicotine is metabolized primarily by the CYP2A6 enzyme to the inactive metabolites cotinine and 3-hydroxycotinine. The ratio of 3-hydroxycotinine to cotinine, referred to as the nicotine metabolite ratio (NMR), is a reproducible measure of CYP2A6 activity that accounts for other genetic and environmental influences on nicotine clearance (e.g., hormonal factors). This biomarker is strongly correlated with nicotine clearance and CYP2A6 genotype amongst smokers of both European and African descent. Slower metabolizers (i.e., those in the lowest quartile of the NMR) have higher quit rates with nicotine patch or placebo treatment than normal metabolizers (i.e., 2nd to 3rd quartiles) and fast metabolizers (i.e., 4th quartile). In our initial study, we found that slower metabolizers demonstrated decreased nAChR availability following overnight abstinence 1. The effects of the NMR on quitting success are greater than the effects of other clinical measures (e.g., the severity of nicotine dependence), such that NMR is the strongest genetically-informed biomarker of smoking cessation. Differences in brain receptor levels secondary to differing durations of nicotine present in the brains of slow versus fast nicotine metabolizers is hypothesized to account for the effects of the NMR on quitting success. We will test this hypothesis by examining the association of variation in nicotine metabolism with differences in brain nAChR availability overnight as well as after two days of nicotine abstinence.