The Role of Nornicotine in protein Glycation

Scripps Research Institute, La Jolla CA

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Abstract

DESCRIPTION (provided by applicant): 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.