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.

Murphy, S. E., Guillermo, C., Thomson, N. M., Carmella, S. G., Wittmann, M., Aldrich, M. C., Cai, Q., Sullivan, S. M., Stram, D. O., Le Marchand, L., Hecht, S. S., Blot, W. J., and Park, S. L. (2024) Association of urinary biomarkers of tobacco exposure with lung cancer risk in African American and White cigarette smokers in the Southern Community Cohort Study, Cancer Epidemiol Biomarkers Prev.

von Weymarn, L. B., Lu, X., Thomson, N. M., LeMarchand, L., Park, S. L., and Murphy, S. E. (2023) Quantitation of ten urinary nicotine metabolites, including 4-hydroxy-4-(3-pyridyl) butanoic acid, a product of nicotine 2'-oxidation, and CYP2A6 activity in Japanese Americans, Native Hawaiians, and Whites, Chem. Res. Toxicol. 36, 313-321.

Cigan, S. S., Murphy, S. E., Stram, D. O., Hecht, S. S., Marchand, L. L., Stepanov, I., and Park, S. L. (2023) Association of urinary biomarkers of smoking-related toxicants with lung cancer incidence in smokers: The Multiethnic Cohort Study, Cancer Epidemiol. Biomarkers Prev. 32, 306-314.

Baurley, J. W., Bergen, A. W., Ervin, C. M., Park, S. L., Murphy, S. E., and McMahan, C. S. (2022) Predicting nicotine metabolism across ancestries using genotypes, BMC Genomics 23, 663.

Murphy, S. E. (2021) Biochemistry of nicotine metabolism and its relevance to lung cancer, J. Biol. Chem. 296, 100722.

Sipe, C. J., Koopmeiners, J. S., Donny, E. C., Hatsukami, D. K., and Murphy, S. E. (2020) UGT2B10 genotype influences serum cotinine levels and is a primary determinant of higher cotinine in African American smokers, Cancer Epidemiol. Biomarkers Prev. 29, 1673-1678.