THE PHARMACOLOGICAL ROLE OF NICOTINE

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The studies described in this proposal focus on the metabolic conversion of nicotine in humans to chemically reactive electrophilic intermediates with bioalkylating and hence cytotoxic potential. Particular emphasis will be placed on the oxidative conversion of nicotine by human lung and liver preparations and by reconstituted human liver cytochrome P-450 preparations to iminium ions which have been characterized previously as nicotine metabolites formed by rodent liver microsomal preparations. Additionally, efforts will be made to characterize nicotine conjugates derived from iminium intermediates in the urine of smokers who have been exposed to nicotine by one of the three routes: cigarettes, nicotine chewing gum, and intravenous administration. These in vivo studies will be conducted in conjunction with ongoing clinical studies designed to evaluate the mutagenic activity of urine obtained from individuals exposed to nicotine by the above three routes. The characterization of the iminium ion pathway for nicotine in humans may be related to the observation that the carcinogenic activity of tobacco smoke condensates is best correlated with nicotine content.