Sharon E. Murphy

Office: 760 Cancer Center

Laboratory: 720 Cancer Center
Lab Telephone: (612) 626-0978

Research Description

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. Nitrosamines require metabolic activation to exert their carcinogenic potential. In animal models, nitrosamines are strikingly tissue specific with regard to tumor induction.  This specificity is believed, at least in part, to be due to tissue specific metabolism.  One of the goals of my laboratory is to characterize the extrahepatic cytochrome P450 enzymes that catalyze the activation of nitrosamines.  We have a number of different P450s expressed and are studying structure activity relationships between these and different nitrosamines.  Two P450s that are >94 % identical catalyze the metabolic activation of the tobacco carcinogen, NNK with strikingly different efficiencies.  Interestingly, the more efficient of these, P450 2A13 is expressed in the human lung and NNK is a 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 UDP-glucuronosyl transferases (UGTs) for nicotine metabolism.  Recently 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.  On-going studies will characterize the mechanism of this inactivation, kinetically and structurally.  In addition, the affect of nicotine-mediated inactivation of these P450s on carcinogen metabolism in smokers is being investigated. 

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 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.

Recent Publications

Berg,J.Z., von Weymarn,L.B., Thompson,E.T., Wickham,K.M., Weisensel,N.A., Hatsukami,D.K., and Murphy,S.E. (2010) UGT2B10 genotype influences nicotine glucuronidation, oxidation and consumption. Cancer Epidemiol Biomarkers Prev, 19, 1423-1431.

Berg JZ, Mason J, Boettcher AJ, Hatsukami DK, and Murphy SE (2010) Nicotine metabolims in African Americans and European Americans: variation in glucuronidation by ethnicity and UGT2B10 haplotype. J.Pharmacol.Exp.Ther. 332, 1423-1431.

Schlicht KE, Zinggeler-Berg J, and Murphy SE (2009) Effect of CYP2A13 Active Site Mutation Asn297Ala on Metabolism of Coumarin and Tobacco-specific Nitrosamines. Drug Metab Dispos. 37:665-671.

Yuan JM, Koh WP, Murphy SE, Fan Y, Wang R, Carmella SG, Han S, Wickham K, Gao YT, Yu MC, and Hecht SS (2009) Urinary levels of tobacco-specific nitrosamine metabolites in relation to lung cancer development in two prospective cohorts of cigarette smokers. Cancer Res. 69:2990-2995.

Derby KS, Cuthrell K, Caberto C, Carmella SG, Franke AA, Hecht SS, Murphy SE, and Le Marchand L (2008) Nicotine metabolism in three ethnic/racial groups with different risks of lung cancer. Cancer Epidemiol Biomarkers Prev 17:3526-3535.

Le Marchand L, Derby KS, Murphy SE, Hecht SS, Hatsukami D, Carmella SG, Tiirikainen M, and Wang H (2008) Smokers with the CHRNA lung cancer-associated variants are exposed to higher levels of nicotine equivalents and a carcinogenic tobacco-specific nitrosamine. Cancer Res. 68:9137-9140.

Murphy SE and von Weymarn LB (2008) Mechanism-Based Inactivation of Cytochrome P450 2A and 2B Enzymes, in Advances in Bioactivation research (Elfarra AA ed) pp 103-131, Springer, New York.

Schlicht KE, Michno N, Smith BD, Scott EE, and Murphy SE (2007) Functional characterization of CYP2A13 polymorphisms. Xenobiotica 37:1439-1449.

Murphy SE, Villalta P, Ho SW, and von Weymarn LB (2007) Analysis of [3',3'-d(2)]-nicotine and [3',3'-d(2)]-cotinine by capillary liquid chromatography-electrospray tandem mass spectrometry. J.Chromatogr.B Analyt.Technol.Biomed.Life Sci. 857:1-8.

von Weymarn LB, Brown KM, and Murphy SE (2006) Inactivation of CYP2A6 and CYP2A13 during nicotine metabolism. J.Pharmacol.Exp.Ther. 316:295-303.

Wong HL, Zhang X, Zhang QY, Gu J, Ding X, Hecht SS, and Murphy SE (2005) Metabolic activation of the tobacco carcinogen 4-(methylnitrosamino)-(3-pyridyl)-1-butanone by cytochrome p450 2A13 in human fetal nasal microsomes. Chem.Res.Toxicol. 18:913-918.