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Sharon E. Murphy

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Title

Sharon E. Murphy
Professor

Department:

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.  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.


Recent Publications

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.

Patel,Y.M., Stram,D.O., Wilkens,L.R., Park,S.L., Henderson,B.E., Le Marchand,L., Haiman,C.A., and Murphy,S.E. (2014) The Contribution of Common Genetic Variation to Nicotine and Cotinine Glucuronidation in Multiple Ethnic/Racial Populations . Cancer Epidemiol Biomarkers Prev, epub.

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.

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.

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. Am.J.Public Health, 103, e54-e59.

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.

Kramlinger,V.M., von Weymarn,L.B., and Murphy,S.E. (2012) Inhibition and inactivation of cytochrome P450 2A6 and cytochrome P450 2A13 by menthofuran, beta-nicotyrine and menthol. Chem.Biol.Interact., 197, 87-92.

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.

Murphy,S.E., von Weymarn,L.B., Schutten,M.M., Kassie,F., and Modiano,J.F. (2011) Chronic nicotine consumption does not influence 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis. Cancer Prev.Res.(Phila), 4, 1752-1760.

Berg,J.Z., Mason,J., Boettcher,A.J., Hatsukami,D.K., and Murphy,S.E. (2010) Nicotine metabolism in African Americans and European Americans: variation in glucuronidation by ethnicity and UGT2B10 haplotype. J.Pharmacol.Exp.Ther., 332, 202-209.

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.

Derby,K.S., Cuthrell,K., Caberto,C., Carmella,S.G., Franke,A.A., Hecht,S.S., Murphy,S.E., 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.

Schlicht,K.E., Michno,N., Smith,B.D., Scott,E.E., and Murphy,S.E. (2007) Functional characterization of CYP2A13 polymorphisms. Xenobiotica, 37, 1439-1449.

von Weymarn,L.B., Brown,K.M., and Murphy,S.E. (2006) Inactivation of CYP2A6 and CYP2A13 during nicotine metabolism. J.Pharmacol.Exp.Ther., 316, 295-303.

 

 

Ph.D., University of Colorado, 1982
Phone Number
(612) 624-7633 Fax: (612) 625-2163
Email Address

murph062@umn.edu

Address
2-127 CCRB
2231 6th St SE
Minneapolis, MN 55455