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Research Abstracts Online
January 2010 - March 2011

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University of Minnesota Twin Cities
Academic Health Center
Masonic Cancer Center

PI: Sharon E. Murphy

Nicotine, Nitrosamines, and P450 2A Enzymes

The tobacco-specific, nicotine-derived nitrosamine NNK is a potent lung carcinogen in rodents and a likely causative agent for lung cancer in smokers. To exert its carcinogenic potential, NNK must be metabolically activated. Activation is catalyzed by cytochrome P450 enzymes (P450s). P450s from the 2A family are among the best catalysts of NNK activation. The metabolism of nicotine, the addictive component of tobacco, is also catalyzed by P450 2A enzymes. This researcher has discovered that nicotine is a mechanism-based inactivator of both human P450 2A enzymes. Mechanism-based inactivation is characterized by the metabolic conversion of a substrate to a reactive intermediate that covalently binds to the enzyme's active site resulting in a loss in enzymatic activity. This project aims to identify the site and structure of the adduct on the P450 2A enzymes. One approach is to use proteomics tools to identify the site and mass of a modified peptide following tryptic digestion of the inactive enzyme. This work will help to elucidate the chemistry that results in mechanism-based inactivation of the P450 2A enzymes.