Tobacco/nicotine, cytochrome P450, and HIV-1

烟草/尼古丁、细胞色素 P450 和 HIV-1

• 批准号: 8254378
• 负责人: Santosh Kumar
• 金额: $ 18.75万
• 依托单位: UNIVERSITY OF MISSOURI KANSAS CITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8254378
• 关键词: AIDS neuropathy; Acetylcysteine; Acquired Immunodeficiency Syndrome; Africa; Alveolar Macrophages; Antioxidants; Attention; Blood; Brain; Butanones; Cameroon; Categories; Cell Line; Centers for Disease Control and Prevention (U.S.); Cessation of life; Clinical; Cotinine; Coumarins; Cytochrome P450; DNA; Development; Dimensions; Foundations; Future; General Population; Genetic Polymorphism; Goals; HIV; HIV-1; Human; Immune response; Individual; Infection; Inflammation; Leukocytes; Link; Liver; Lung; Malignant neoplasm of esophagus; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Measures; Mediating; Messenger RNA; Metabolic Pathway; Metabolism; Methionine; Methoxsalen; Microglia; Modeling; N' -nitrosonornicotine; National Institute of Drug Abuse; Neurons; Nicotine; Oxidative Stress; Population; Prevalence; Proteins; Reactive Oxygen Species; Recruitment Activity; Reporting; Research; Risk; Role; Smoker; Smoking; Substance of Abuse; Superoxide Dismutase; Techniques; Testing; Therapeutic Agents; Tobacco; Tobacco use; Tryptamines; U937 Cells; Virus; Woman; Work; alpha benzopyrone; antiretroviral therapy; catalase; cellular targeting; cigarette smoking; comparative; design; inhibitor/antagonist; macrophage; monocyte; non-smoker; novel; novel therapeutics; public health relevance; response; smoking prevalence

DESCRIPTION (provided by applicant): The potential impact of cigarette smoking in HIV scenario can be gauged from the fact that the prevalence of smoking is estimated to be 50-70% in HIV+ population compared to 20% in the general population. Until recently, little attention was paid to the potential interaction between smoking and HIV-1/AIDS. Smoking and its main constituent, nicotine have been shown to enhance HIV-1 replication in alveolar macrophages and microglia, decrease immune responses, and decreased responses to antiretroviral therapy (ART). However, very little is known about the mechanism(s) by which nicotine causes these effects. Nicotine, its major metabolite, cotinine, and other important tobacco-specific compounds are predominantly metabolized by cytochrome P450 2A6 (CYP2A6), especially in the liver, and by lung-specific CYP2A13. This metabolic pathway is thought to increase oxidative stress and inflammation, resulting in liver damage, as well as lung, esophageal, and pancreatic cancers. Several studies, including ours, demonstrate that CYP2A6 is highly expressed in human monocyte-derived macrophages. Our preliminary studies show that CYP2A6 is induced by nicotine in U937 cell lines (HIV-1 model cell lines for macrophages). However, their clinical implications are unknown. Macrophages are one of the major cellular targets of HIV-1, crucial virus reservoirs, and carriers of HIV-1 infection to the brain (NeuroAIDS). Our goal is to examine the role of nicotine in CYP2A6-induced oxidative stress and HIV-1 replication in macrophages. Our hypothesis is that nicotine enhances HIV-1 replication in macrophages through CYP2A6-mediated nicotine metabolism and oxidative stress. To test the hypothesis, the study is designed with two specific aims. Specific Aim 1: To examine the role of nicotine on CYP2A6-mediated oxidative stress and HIV-1 replication in human primary macrophages. Specific Aim 2: To determine the effect of smoking on CYP2A6 expression, oxidative stress, and HIV-1 replication in HIV+ smokers. Upon successful completion of this project, we will have tested our hypothesis that nicotine enhances HIV-1 replication through CYP2A6-mediated oxidative stress in human macrophages. This would provide the first evidence of the effect of nicotine on HIV-1 replication in macrophages and the mechanism by which it occurs. This novel work would provide a new dimension in HIV-1/nicotine related research, and would provide an opportunity to develop novel therapeutic agents to treat HIV+ smokers effectively. PUBLIC HEALTH RELEVANCE: The proposal will examine the role of smoking/nicotine on CYP2A6-mediated oxidative stress in HIV-1 replication. The proposal would provide a new dimension to link substances of abuse, especially tobacco use and HIV-1, which is one of the major objectives of NIDA. In long term, this would provide an opportunity to develop novel therapeutic agents to treat HIV+ smokers effectively.

描述（由申请人提供）：可以从HIV情况下吸烟的潜在影响，这是因为据估计吸烟率估计在HIV+人群中为50-70％，而普通人群为20％。直到最近，很少关注吸烟与HIV-1/艾滋病之间的潜在相互作用。吸烟及其主要成分尼古丁已被证明可增强肺泡巨噬细胞和小胶质细胞中的HIV-1复制，减少免疫反应，并减少对抗逆转录病毒疗法（ART）的反应。但是，关于尼古丁引起这些作用的机制知之甚少。尼古丁，其主要代谢产物，可替宁和其他重要的烟草特异性化合物主要由细胞色素P450 2A6（CYP2A6）代谢，尤其是在肝脏和肺特异性CYP2A13中。该代谢途径被认为会增加氧化应激和炎症，从而导致肝脏损伤，以及肺，食管和胰腺癌。包括我们的几项研究表明，CYP2A6在人类单核细胞衍生的巨噬细胞中高度表达。我们的初步研究表明，CYP2A6是由U937细胞系中的尼古丁（HIV-1模型细胞系）诱导的。但是，它们的临床意义尚不清楚。巨噬细胞是HIV-1的主要细胞靶标之一，关键的病毒储存库和HIV-1感染的载体（神经剂）。我们的目标是检查尼古丁在CYP2A6诱导的氧化应激和HIV-1在巨噬细胞中的作用。我们的假设是，尼古丁通过CYP2A6介导的尼古丁代谢和氧化应激增强了巨噬细胞中的HIV-1复制。为了检验该假设，该研究的设计具有两个特定的目的。具体目的1：检查尼古丁在人类原发性巨噬细胞中CYP2A6介导的氧化应激和HIV-1复制中的作用。具体目的2：确定吸烟对HIV+吸烟者中CYP2A6表达，氧化应激和HIV-1复制的影响。成功完成该项目后，我们将检验我们的假设，即尼古丁通过人类巨噬细胞中的CYP2A6介导的氧化应激增强了HIV-1复制。这将提供第一个证据，证明尼古丁对巨噬细胞中HIV-1复制的影响及其发生的机制。这项新颖的工作将在HIV-1/尼古丁相关的研究中提供一个新的维度，并将为开发新型治疗剂有效治疗艾滋病毒+吸烟者提供机会。 公共卫生相关性：该提案将研究吸烟/尼古丁在HIV-1复制中氧化应激中的作用。该提案将为滥用滥用的物质（尤其是烟草使用和HIV-1）提供一个新的维度，这是NIDA的主要目标之一。从长远来看，这将为开发新颖的治疗剂提供有效治疗艾滋病毒+吸烟者的机会。

项目成果

Cytochrome P450-Mediated Phytoremediation using Transgenic Plants: A Need for Engineered Cytochrome P450 Enzymes.

使用转基因植物进行细胞色素 P450 介导的植物修复：需要工程细胞色素 P450 酶。

• DOI: 10.4172/2157-7463.1000127
• 发表时间: 2012
• 期刊: Journal of petroleum & environmental biotechnology
• 作者: Kumar,Santosh;Jin,Mengyao;Weemhoff,JamesL
• 通讯作者: Weemhoff,JamesL

Analysis of Cytochrome P450 Conserved Sequence Motifs between Helices E and H: Prediction of Critical Motifs and Residues in Enzyme Functions.

螺旋 E 和 H 之间的细胞色素 P450 保守序列基序分析：酶功能中关键基序和残基的预测。

• DOI: 10.4172/2157-7609.1000110
• 发表时间: 2011
• 期刊: Journal of drug metabolism & toxicology
• 作者: Oezguen,Numan;Kumar,Santosh
• 通讯作者: Kumar,Santosh

Challenges and Opportunities of Cytochrome P450-Mediated Phytoremediation.

细胞色素 P450 介导的植物修复的挑战和机遇。

• DOI: 10.4172/2157-7463.s4-e001
• 发表时间: 2012
• 期刊: Journal of petroleum & environmental biotechnology
• 作者: Kumar,Santosh

Effect of mild-to-moderate smoking on viral load, cytokines, oxidative stress, and cytochrome P450 enzymes in HIV-infected individuals.

• DOI: 10.1371/journal.pone.0122402
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Ande A;McArthur C;Ayuk L;Awasom C;Achu PN;Njinda A;Sinha N;Rao PS;Agudelo M;Nookala AR;Simon S;Kumar A;Kumar S
• 通讯作者: Kumar S

A LC-MS/MS method for concurrent determination of nicotine metabolites and role of CYP2A6 in nicotine metabolism in U937 macrophages: implications in oxidative stress in HIV + smokers.

• DOI: 10.1007/s11481-011-9283-6
• 发表时间: 2012-03
• 期刊: JOURNAL OF NEUROIMMUNE PHARMACOLOGY
• 影响因子: 6.2
• 作者: Jin, Mengyao;Earla, Ravinder;Shah, Ankit;Earla, Rajya L.;Gupte, Raeesa;Mitra, Ashim K.;Kumar, Anil;Kumar, Santosh
• 通讯作者: Kumar, Santosh