Cytochrome P450 in Nicotine Metabolism

尼古丁代谢中的细胞色素 P450

• 批准号: 6619601
• 负责人: SHARON E MURPHY
• 金额: $ 16.22万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6619601
• 关键词: alpha benzopyrone; chemical carcinogen; chemical carcinogenesis; cytochrome P450; drug metabolism; enzyme activity; esophagus; laboratory mouse; laboratory rat; lung; microsomes; mucosa; nicotine

DESCRIPTION: (PROVIDED BY APPLICANT) Nicotine is well established to be the addictive agent in tobacco, and its metabolites are chemically well described. Surprisingly, the specific enzymes responsible for nicotine metabolism are rather poorly characterized. In this proposal the role of individual P450s in the metabolism of nicotine and cotinine will be investigated. In most smokers the majority of nicotine is metabolized to cotinine. The first step of this pathway is nicotine 5'- oxidation. Cotinine is metabolized to trans-3'-hydroxycotinine, the major nicotine metabolite excreted by smokers. P450 2A6 is reported to be responsible for both the 5'-oxidation of nicotine and the 3'-hydroxylation of cotinine. Nicotine is not exclusively metabolized by P450 2A6, and P450 2A6-catalyzed nicotine metabolism is not specific for 5'-oxidation. We have reported that both P450 2A6 and human liver microsomes (HLM) catalyze the 2'-oxidation of nicotine. The product of this reaction is the precursor of the lung carcinogen, NNK. P450 2A13, which is closely related to P450 2A6, is expressed in the lung and is an efficient catalyst of both nicotine 5'-oxidation and NNK metabolic activation. The extent of nicotine 2'-oxidation by this enzyme is unknown. P450 2A 13 could prove to be an important enzyme in NNK induced lung carcinogenesis in smokers. P450 2B6 is also a catalyst of nicotine 5'-oxidation and appears to contribute to nicotine metabolism by HLM. The antismoking agent bupropion is metabolized by P450 2B6. It is proposed that one mechanism of bupropion's action may be its inhibition of nicotine metabolism. Studies to investigate the importance of nicotine metabolism in smoking and the use of metabolism inhibitors to modify smoking behavior are ongoing. For these studies to succeed and to optimize the use of pharmacological agents to help reduce smoking, it is critical to understand all the enzymes involved in nicotine metabolism and to characterize the products of each pathway. The goals of this proposal are to determine the contribution of P450 2A6 and other hepatic P450s to nicotine and cotinine metabolism, to investigate the metabolism of nicotine and cotinine by human lung microsomes and P450s present in the lung, and to determine the specificity of that metabolism by the important P450s in the lung and liver. The hypotheses to be tested are that both nicotine and cotinine are metabolized by P450s other than P450 2A6 and that the specificity of that metabolism will vary among, P450s. The specific aims are: 1) .to determine the role of human hepatic P450s other than P450 2A6 in both nicotine and cotinine metabolism, 2) to characterize the metabolism of nicotine and cotinine by human lung microsomes, 3) to completely characterize the products of nicotine and cotinine metabolism by human lung microsomes, 4) to determine whether bupropion inhibits any of the pathways of nicotine metabolism in HLM.

描述：（由申请人提供）尼古丁是公认的 烟草中的成瘾剂及其代谢物在化学上已有详细描述。 令人惊讶的是，负责尼古丁代谢的特定酶是 特征相当差。在此提案中，各个 P450 的作用 将研究尼古丁和可替宁的代谢。对于大多数吸烟者来说 大部分尼古丁被代谢为可替宁。这个的第一步 途径是尼古丁5'-氧化。可替宁代谢为 反式3'-羟基可替宁，吸烟者排泄的主要尼古丁代谢物。 据报道，P450 2A6 负责尼古丁的 5'-氧化 和可替宁的3'-羟基化。尼古丁不完全被代谢 由 P450 2A6 催化，并且 P450 2A6 催化的尼古丁代谢不具有特异性 5'-氧化。我们报道了 P450 2A6 和人肝微粒体 (HLM) 催化尼古丁的 2'-氧化。该反应的产物是 肺癌致癌物NNK的前体。 P450 2A13，密切相关 P450 2A6，在肺中表达，是两者的有效催化剂 尼古丁 5'-氧化和 NNK 代谢激活。尼古丁的含量 这种酶的 2'-氧化作用尚不清楚。 P450 2A 13 可能被证明是 NNK 诱导吸烟者肺癌发生的重要酶。 P450 2B6 是 也是尼古丁 5'-氧化的催化剂，似乎有助于尼古丁的产生 HLM 代谢。戒烟剂安非他酮由 P450 2B6 代谢。 有人提出，安非他酮的作用机制之一可能是其抑制作用 尼古丁代谢。调查尼古丁重要性的研究 吸烟中的代谢以及使用代谢抑制剂来改变吸烟 行为正在进行中。为了使这些研究取得成功并优化使用 为了帮助减少吸烟，了解所有药物至关重要 参与尼古丁代谢的酶并表征其产物 每条路径。该提案的目标是确定以下人员的贡献： P450 2A6 和其他肝脏 P450 参与尼古丁和可替宁代谢， 研究人肺微粒体对尼古丁和可替宁的代谢 和 P450 存在于肺部，并确定其特异性 由肺和肝脏中重要的 P450 进行代谢。假设是 经测试，尼古丁和可替宁均由 P450 代谢，除了 P450 2A6 并且该代谢的特异性在 P450 之间会有所不同。 具体目标是： 1).确定人肝P450s的其他作用 尼古丁和可替宁代谢均优于 P450 2A6，2) 来表征 人肺微粒体对尼古丁和可替宁的代谢，3) 完全 表征人肺尼古丁和可替宁代谢产物 微粒体，4) 确定安非他酮是否抑制任何途径 HLM 中的尼古丁代谢。