NUTRACEUTICALS, NITRIC OXIDE-DERIVED OXIDANTS, AND ZENOBIOTIC METABOLISM

营养药品、一氧化氮衍生的氧化剂和Zenobiotic代谢

• 批准号: 7381338
• 负责人: RAO M UPPU
• 金额: $ 5.86万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7381338
• 关键词: NUTRACEUTICALS; NITRIC; OXIDE; DERIVED; OXIDANTS

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Elucidating the mechanisms of oxidative transformation of xenobiotics by nitric oxide-derived oxidants (NOx) and the formation of electrophilic intermediates are the primary focus of the proposed investigation. The three major species of NOx, namely, nitrogen dioxide, carbonate radical, and peroxynitrite represent an important class of oxidants that are produced during the down regulation of nitric oxide in biological environments. It is our hypothesis that NOx cause oxidative transformation and metabolite activation of xenobiotics, thereby contributing to cellular oxidant stress. We envision two different scenarios that can explain oxidative transformation of xenobiotics. Some xenobiotics that contain a hetero atom (N, S, or P) in its low oxidation state can undergo oxidative transformation by NOx directly, while others require prior metabolism by enzymes of the cytochrome P450 system (CYP 450), flavin monooxygenases (FMOs), or myeloperoxidase (MPO). To address these divergent situations, the study is divided into two parts. In the first part, we will examine the direct reactions of NOx with xenobiotics (Specific Aim 1). In the second part, we will study the reactions of NOx with xenobiotic metabolites formed in reactions of xenobiotics with FMOs, MPOs, and CYP 450 (Specific Aim 2). We will employ CYP 450 that are either consitutive or induced by Aroclor 1254, 3-methylcholanthrene, or phenobarbital. In both specific aim 1 and 2, emphasis will be placed on the formation of small but significant yields of electrophilic intermediates that are capable of binding DNA and other macromolecules or have the ability to cause depletion of cellular antioxidants. Oxidative biotransformation of xenobiotics resulting in the formation of electrophilic intermediates by NOx may provide newer avenues for understanding the mechanism of toxicity induced by environmental pollutants and pharmaceuticals. The proposed study will add to a further understanding of the long-term toxicological consequences of NOx-xenobiotic interactions and specifically their role in establishment of cellular oxidative stress.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构适用于该中心，这不一定是调查员的机构。阐明一氧化氮衍生的氧化剂（NOX）对异生元的氧化转化的机制和亲电中间体的形成是拟议研究的主要重点。 NOX的三个主要物种，即二氧化氮，碳酸盐自由基和过氧亚硝酸盐代表了在生物环境中对一氧化氮调节期间产生的一类重要氧化剂。我们的假设是，NOX会导致异种生物的氧化转化和代谢物激活，从而有助于细胞氧化剂应激。我们设想两个不同的情况，可以解释异种生物的氧化转化。一些含有异氧化原子（N，S或P）低氧化态的异生元可以直接通过NOX进行氧化转化，而其他人则需要通过细胞色素P450系统（CYP 450）的酶先验代谢，Flavin单基因酶（FMOS）（FMOS），或肌蛋白酶（Myeloperoperoperoperoperoxidase）（mpo）（mpo）。为了解决这些不同的情况，该研究分为两个部分。在第一部分中，我们将检查NOX与异种生物的直接反应（特定目标1）。在第二部分中，我们将研究NOX与异种生物代谢产物与FMOS，MPOS和CYP 450的反应形成的反应（特定AIM 2）。我们将使用Aroclor 1254、3-甲基胆碱或苯巴比妥诱导的CYP 450。在特定的目标1和2中，将重点放在能够结合DNA和其他大分子或具有引起细胞抗氧化剂消耗的能力的亲电中间体的小但显着的产率上。异种生物的氧化生物转化导致NOX形成的亲电中间体形成，可能会提供更新的途径，以理解由环境污染物和药品引起的毒性机制。拟议的研究将进一步了解NOX-六培养基相互作用的长期毒理学后果，特别是它们在建立细胞氧化应激中的作用。