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.
Selected References (2011-2018)
Murphy SE, von Weymarn LB, Parenteau M, Stepanov I, Tiirikainen M, LeMarchand L, Park SL. Influence of UGT2B10 Genotype on Urinary Excretion of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol- N-glucuronide by African American Smokers. Chem Res Toxicol. 2018;31(3):168-75.
Murphy SE, Park SL, Balbo S, Haiman CA, Hatsukami DK, Patel Y, Peterson LA, Stepanov I, Stram DO, Tretyakova N, Hecht SS, Le Marchand L. Tobacco biomarkers and genetic/epigenetic analysis to investigate ethnic/racial differences in lung cancer risk among smokers. NPJ Precis Oncol. 2018;2:17.
Hatsukami DK, Luo X, Jensen JA, al'Absi M, Allen SS, Carmella SG, Chen M, Cinciripini PM, Denlinger-Apte R, Drobes DJ, Koopmeiners JS, Lane T, Le CT, Leischow S, Luo K, McClernon FJ, Murphy SE, Paiano V, Robinson JD, Severson H, Sipe C, Strasser AA, Strayer LG, Tang MK, Vandrey R, Hecht SS, Benowitz NL, Donny EC. Effect of Immediate vs Gradual Reduction in Nicotine Content of Cigarettes on Biomarkers of Smoke Exposure: A Randomized Clinical Trial. JAMA. 2018;320(9):880-91.
Dator R, von Weymarn L, Villalta PW, Hooyman CJ, Maertens LA, Upadhyaya P, Murphy SE, Balbo S. In Vivo Stable Isotope Labeling and Mass Spectrometry-Based Metabolic Profiling of a Potent Tobacco-Specific Carcinogen in Rats. Anal Chem. 2018.
Murphy SE. Nicotine Metabolism and Smoking: Ethnic Differences in the Role of P450 2A6. Chem Res Toxicol. 2017;30(1):410-9.
Yuan JM, Nelson HH, Carmella SG, Wang R, Kuriger-Laber J, Jin A, Adams-Haduch J, Hecht SS, Koh WP, Murphy SE. CYP2A6 genetic polymorphisms and biomarkers of tobacco smoke constituents in relation to risk of lung cancer in the Singapore Chinese Health Study. Carcinogenesis. 2017;38(4):411-8.
Murphy SE, Sipe CJ, Choi K, Raddatz LM, Koopmeiners JS, Donny EC, Hatsukami DK. Low Cotinine Glucuronidation Results in Higher Serum and Saliva Cotinine in African American Compared to White Smokers. Cancer Epidemiol Biomarkers Prev. 2017;26(7):1093-9.
Park SL, Murphy SE, Wilkens LR, Stram DO, Hecht SS, Le Marchand L. Association of CYP2A6 activity with lung cancer incidence in smokers: The multiethnic cohort study. PLoS One. 2017;12(5):e0178435.
Yuan JM, Nelson HH, Butler LM, Carmella SG, Wang R, Kuriger-Laber JK, Adams-Haduch J, Hecht SS, Gao YT, Murphy SE. Genetic determinants of cytochrome P450 2A6 activity and biomarkers of tobacco smoke exposure in relation to risk of lung cancer development in the Shanghai cohort study. Int J Cancer. 2016;138(9):2161-71.
Park SL, Tiirikainen MI, Patel YM, Wilkens LR, Stram DO, Le Marchand L, Murphy SE. Genetic determinants of CYP2A6 activity across racial/ethnic groups with different risks of lung cancer and effect on their smoking intensity. Carcinogenesis. 2016;37(3):269-79.
von Weymarn LB, Thomson NM, Donny EC, Hatsukami DK, Murphy SE. Quantitation of the Minor Tobacco Alkaloids Nornicotine, Anatabine, and Anabasine in Smokers' Urine by High Throughput Liquid Chromatography-Mass Spectrometry. Chem Res Toxicol. 2016;29(3):390-7.
Denlinger RL, Smith T, Murphy SE, Koopmeiners JS, Benowitz NL, Hatsukami DK, Pacek LR, Collino C, Cwalina SN, Donny EC. Quantification of nicotine and anatabine exosure from very low nicotine content cigarettes. Tobacco Regulatory Science. 2016;2(2):186-203.
Patel YM, Park SL, Han Y, Wilkens LR, Bickeboller H, Rosenberger A, Caporaso N, Landi MT, Bruske I, Risch A, Wei Y, Christiani DC, Brennan P, Houlston RS, McKay J, McLaughlin J, Hung RJ, Murphy SE, Stram DO, Amos CI, Le Marchand L. Novel Association of Genetic Markers Affecting CYP2A6 activity and Lung Cancer Risk. Cancer Res. 2016;76(19):5768-76.
Patel YM, Stram DO, Wilkens LR, Park SS, Henderson BE, Le Marchand L, Haiman CA, Murphy SE. The contribution of common genetic variation to nicotine and cotinine glucuronidation in multiple ethnic/racial populations. Cancer Epidemiol Biomarkers Prev. 2015;24(1):119-27.
Wang H, Park SL, Stram DO, Haiman CA, Wilkens LR, Hecht SS, Kolonel LN, Murphy SE, Le Marchand L. Associations Between Genetic Ancestries and Nicotine Metabolism Biomarkers in the Multiethnic Cohort Study. Am J Epidemiol. 2015;182(11):945-51.
Murphy, S. E., Park, S. S., Thompson, E. F., Wilkens, L. R., Patel, Y., Stram, D. O., and Le Marchand, L. (2014) Nicotine N-glucuronidation relative to N-oxidation and C-oxidation and UGT2B10 genotype in five ethnic/racial groups. Carcinogenesis 35, 2526-2533.
Joseph, A. M., Spector, L. G., Wickham, K. M., Janis, G., Winickoff, J. P., Lindgren, B., and Murphy, S. E. (2013) Biomarker evidence of tobacco smoke exposure in children participating in lead screening. American Journal of Public Health 103, e54-e59.
Murphy, S. E., Wickham, K. M., Lindgren, B. R., Spector, L. G., and Joseph, A. (2013) Cotinine and trans 3'-hydroxycotinine in dried blood spots as biomarkers of tobacco exposure and nicotine metabolism. J. Expo. Sci. Environ. Epidemiol 23, 513-518.
Bloom, A. J., von Weymarn, L. B., Martinez, M., Bierut, L. J., Goate, A., and Murphy, S. E. (2013) The contribution of common UGT2B10 and CYP2A6 alleles to variation in nicotine glucuronidation among European Americans. Pharmacogenet. Genomics 23, 706-716.
von Weymarn, L. B., Retzlaff, C., and Murphy, S. E. (2012) CYP2A6 and CYP2A13-catalyzed metabolism of the nicotine delta 1'(5') iminium ion. J. Pharmacol. Exp. Ther 343, 307-315
Bloom, J., Hinrichs, A. L., Wang, J. C., von Weymarn, L. B., Bierut, L. J., Goate, A., and Murphy, S. E. (2011) The Contribution of Common CYP2A6 Alleles to Variation in Nicotine Metabolism Among European Americans. Pharmacogenet. Genomics 21, 403-416.