Cytochrome P450 in Nicotine Metabolism

尼古丁代谢中的细胞色素 P450

• 批准号: 6758558
• 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 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6758558
• 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）尼古丁已被公认为 烟草中的添加剂及其代谢物在化学上有很好的描述。 令人惊讶的是，负责尼古丁代谢的特定酶是 相当不好描述。在本提案中，单个P450在 将研究尼古丁和可替宁的代谢。大多数吸烟者 大部分尼古丁被代谢成可替宁。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，吸烟者排出的主要尼古丁代谢物。 据报道，P450 2A 6负责尼古丁的5 '-氧化 和可替宁的3’-羟基化。尼古丁并不完全被代谢 通过P450 2A 6，P450 2A 6催化的尼古丁代谢对 5 '-氧化。我们已经报道了P450 2A 6和人肝微粒体 (HLM)催化尼古丁的2 '-氧化。该反应的产物为 肺癌致癌物NNK的前体P450 2A 13，与 到P450 2A 6，在肺中表达，是两者的有效催化剂。 尼古丁5 '-氧化和NNK代谢活化。尼古丁的含量 这种酶的2 '-氧化作用是未知的。P450 2A 13可以证明是一种 NNK诱导吸烟者肺癌发生中的重要酶。P450 2B 6是 也是尼古丁5 '-氧化的催化剂，似乎有助于尼古丁 通过HLM进行代谢。抗吸烟剂安非他酮由P450 2B 6代谢。 安非他酮的作用机制之一可能是抑制 尼古丁的代谢。研究尼古丁的重要性 吸烟中的代谢和代谢抑制剂在改变吸烟中的用途 行为正在进行中。为了使这些研究取得成功并优化使用 药物，以帮助减少吸烟，这是至关重要的是要了解所有 参与尼古丁代谢的酶，并表征 每一条路。本提案的目标是确定以下方面的贡献： P450 2A 6和其他肝脏P450对尼古丁和可替宁代谢， 研究尼古丁和可替宁在人肺微粒体中的代谢 和P450，并确定其特异性， P450在肺和肝中的重要代谢。假设是 测试结果表明，尼古丁和可替宁均由P450代谢，而不是 P450 2A 6，并且该代谢的特异性将在P450之间变化。 具体目的是：1）确定人肝P450的作用， 比P450 2A 6在尼古丁和可替宁代谢中，2）表征 尼古丁和可替宁通过人肺微粒体的代谢，3）完全 尼古丁和可替宁经人肺代谢产物的特征 微粒体，4）以确定安非他酮是否抑制任何途径， HLM中的尼古丁代谢。