Despite ample evidence supporting the negative effects of tobacco abuse, cigarettes and nicotine addiction remain one of the leading causes of preventable death in the United States. Both the systemic and psychoactive effects of nicotine are well-documented, yet little research has been devoted to the physiological effects of nornicotine, a minor psychoactive metabolite. We propose that nornicotine is capable of participating in the formation of glycation proteins, and that the presence of nornicotine both natively in tobacco and as a nicotine metabolite could have significant implications in a number of tobacco-related disease states. In order to explore the role of nornicotine in protein glycation, a multidisciplinary study is proposed. First, using synthetic organic chemistry, we will determine the ability of nornicotine to form Amadori products in vitro. Concurrently, we will develop a rapid immunoassay for the detection of nornicotine-derived glycated proteins. To facilitate this, we will also develop novel haptens for the preparation of new antibodies with enhanced specificity for these glycation products. This assay will be tested using a behavioral rat model of chronic exposure to nicotine, nornicotine, and the nornicotine-derived Amadori product. Second, to establish the major route of introduction of Amadori products, we will explore both the rate of in vivo synthesis of the Amadori product versus the inherent proportion of this compound that exists in cured tobacco. We believe that the proposed studies will provide a molecular link between disease and tobacco abuse as well as a dramatic insight into the unprecedented ability of a secondary nicotine metabolite to perform chemistry in vivo.
| Dickerson, Tobin J; Lovell, Timothy; Meijler, Michael M et al. (2004) Nornicotine aqueous aldol reactions: synthetic and theoretical investigations into the origins of catalysis. J Org Chem 69:6603-9 |
| Dickerson, Tobin J; Yamamoto, Noboru; Ruiz, Diana I et al. (2004) Immunological consequences of methamphetamine protein glycation. J Am Chem Soc 126:11446-7 |
| Dickerson, Tobin J; Yamamoto, Noboru; Janda, Kim D (2004) Antibody-catalyzed oxidative degradation of nicotine using riboflavin. Bioorg Med Chem 12:4981-7 |
| Dickerson, Tobin J; Janda, Kim D (2003) Glycation of the amyloid beta-protein by a nicotine metabolite: a fortuitous chemical dynamic between smoking and Alzheimer's disease. Proc Natl Acad Sci U S A 100:8182-7 |
| Gambs, Celine; Dickerson, Tobin J; Mahajan, Suresh et al. (2003) High-resolution diffusion-ordered spectroscopy to probe the microenvironment of JandaJel and Merrifield resins. J Org Chem 68:3673-8 |
