Research Program: Carcinogenesis & Chemoprevention
Professor, Department of Biochemistry, Molecular Biology and Biophysics

murph062@umn.edu
612-624-7633 — office
612-626-0978 — lab
Preferred method of contact: e-mail

Research Interests

Nicotine is the major addictive agent in tobacco. It is quickly converted to a non-addictive metabolite, cotinine. Cotinine, in turn is further metabolized to trans 3'-hydroxycotinine and its glucuronide. Studies in our laboratory have characterized P450 2A6 and P450 2A13-catalyzed metabolism of both nicotine and cotinine. P450 2A6, which is present in human liver is 94% identical to the extrahepatic enzyme, P450 2A13 found in the lung. We recently determined that both enzymes are inactivated during nicotine metabolism, and are investigating the mechanism of this inactivation. P450 2A6 and P450 2A13 are also catalysts of the metabolic activation of the tobacco specific carcinogens NNN and NNK. However, despite the similarity of these two enzymes, they catalyze NNK metabolism with strikingly different efficiencies. Metabolism by site directed mutagens of these two enzymes are being studied to investigate these structure activity relationship. Polymorphisms of both P450 2A6 and P450 2A13 exist and we and others are studying the influence of enzyme variants on nicotine and nitrosamine metabolism.

In addition, collaborative studies on nicotine metabolism in smokers are on-going to investigate the influence of individual differences in nicotine metabolism on smoking behavior and nicotine dependence.

Selected Publications

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

Jalas JR, Hecht SS, Murphy SE. Cytochrome P450 enzymes as catalysts of metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific carcinogen. Chem Res Toxicol. 2005;18:95-110.

Murphy SE, Raulinaitis V, Brown KM. Nicotine 5'-oxidation and methyl oxidation by P450 2A enzymes. Drug Metab Dispos. 2005;13:1166-1173.

Brown KM, von Weymarn LB, Murphy SE. Identification of N-(hydroxymethyl)-norcotinine as a major product of cytochrome P450 2A6, but not cytochrome P450 2A13-catalyzed cotinine metabolism. Chem Res Toxicol. 2005;18:1792-1798.

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

Murphy SE, Villalta P, Ho SW, von Weymarn LB. 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, 2007;857:1-8.

Zhang X, D'Agostino J, Wu H, Zhang QY, von Weymarn L, Murphy SE, Ding X. CYP2A1 3: variable expression and role in human lung microsomal metabolic activation of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. J Pharmacol Exp Ther, 2007;323:570-578.