Research Interests   Carcinogen and nicotine metabolism

We study the cytochrome P450 catalyzed 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. For example, nitrosamines that differ by only one methyl group may induce tumors selectively in two different tissues. 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 P450s that catalyze the activation of nitrosamines. We have a number of different P450s expressed and are studying structure activity relationships between these enzymes 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 is expressed in the human lung and NNK is a lung carcinogen.

Nicotine is metabolized by some of the same enzymes, and a second goal of my laboratory is to characterize those P450s involved in nicotine metabolism. We are investigating the specificity and selectivity of particular P450s for nicotine oxidation. In addition, the effect of polymorphisms in these P450s on smoking behavior and nicotine addiction is being investigated. Ultimately, these data may be applicable to epidemiology studies.

Murphy, S. E., Raulinaitis, V., and Brown, K. M. Nicotine 5'-oxidation and methyl oxidation by P450 2A enzymes. Drug Metab Dispos., in press: 2005.

Jalas, J. R., Hecht, S. S., and Murphy, S. E. Cytochrome P450 enzymes as catalysts of metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific carcinogen. Chem.Res.Toxicol ., 18 : 95-110, 2005

Wong, H. L., Murphy, S. E., and Hecht, S. S. Cytochrome P450 2A-catalyzed metabolic activation of structurally similar carcinogenic nitrosamines: N' -nitrosonornicotine enantiomers, N -nitrosopiperidine, and N -nitrosopyrrolidine. Chem.Res.Toxicol ., 18 : 61-69, 2005.

Jalas, J. R., Seetharaman, M., Hecht, S. S., and Murphy, S. E. Molecular modeling of CYP2A enzymes: application to metabolism of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Xenobiotica, 34 : 515-533, 2004.

Jalas, J. R., Ding, X., and Murphy, S. E. Comparative metabolism of the tobacco-specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) by rat cytochrome P450 2A3 and human cytochrome P450 2A13. Drug Metabol.Dispos ., 31 : 1199-1202, 2003.

Hecht, S.S., Hochalter, J.B., Villalta, P.W. and Murphy, S.E. (2000) 2'-Hydroxylation of nicotine by cytochrome P450 2A6 and human liver microsomes: Formation of a lung carcinogen precursor. Proc. Natl. Acad. Sci . 97 :12493-12497