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., 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-pyr
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.