THE PHARMACOLOGICAL ROLE OF NICOTINE

本提案中描述的研究重点是 尼古丁在人体内转化为化学反应性亲电中间体， 生物烷基化并因此具有细胞毒性潜力。 将特别强调 人体肺和肝脏对尼古丁的氧化转化 制剂和复溶人肝细胞色素P-450制剂 亚胺鎓离子之前被表征为尼古丁 啮齿动物肝微粒体制剂形成的代谢物。 此外，本发明还 将努力表征衍生自以下物质的尼古丁缀合物： 吸烟者尿中的亚胺中间体， 尼古丁的三种途径之一：香烟，尼古丁口香糖， 静脉给药。 这些体内研究将在 结合正在进行的临床研究，旨在评估 从暴露于尼古丁的个体中获得的尿液的致突变活性 以上三条路线。 亚胺离子途径的表征 尼古丁在人类中的作用可能与观察到的 烟草烟雾冷凝物的致癌活性与 尼古丁含量

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.