FUNCTIONAL SIGNIFICANCE OF CYTOCHROME P450 CYCLOOXYGENASE

细胞色素 P450 环加氧酶的功能意义

• 批准号: 6653341
• 负责人: JOHN C MC GIFF
• 金额: $ 31.48万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6653341
• 关键词: adrenalectomy; angiotensin II; arachidonate; cytochrome P450; dietary sodium; eicosanoid metabolism; enzyme activity; enzyme mechanism; glucocorticoids; hormone regulation /control mechanism; hypertension; isolation perfusion; kidney function; laboratory rat; mass spectrometry; nitric oxide; nitric oxide synthase; nutrition related tag; prostaglandin endoperoxide synthase; protein protein interaction; tumor necrosis factor alpha; vasomotion

20-hydroxyeicosatetraenoic acid (20-HETE) is the principal eicosanoid of key renal structures where it serves an essential component in the regulation of renal vascular and tubular function. In view of the importance of 20-HETE to renal function, the identification and characterization of those factors that govern production and activity of 20-HETE assume a high priority as they determine the depth and breadth of the renal actions of the eicosanoid. Cyclooxygenases (COX-1 and COX 2) and nitric oxide synthases (NOS) have been identified as being central to the regulation of 20-HETE metabolism and production, respectively. Three Aims will address the postulated importance of COX and NO to 20-HETE levels and activities in the kidney. AIM 1 makes of the AII infusion model of hypertension to determine relationship and possible interactions of cytokines, NO and COX (both-1 and -2) that affect production and biological activities of 20-HETE. Aim 2 draws upon the relatively selective effect of high salt intake on NO production and low salt intake on cortical COX-2 expression in order to study their separate effects on 20-HETE tissue levels and spectrum of biological activities of 20-HETE metabolites in the cortex. AIM 3 addresses the powerful negative effect of glucocorticoids on COX- 2 expression in the TAL in order to define interactions involving TNF and COX-2 (and possibly iNOS) post-adrenal and to relate one or more of these factors to a postulated depression of CYP450 AA metabolism and to changes in renal function.

20-羟基二十碳四烯酸（20-HETE）是肾脏关键结构的主要类二十碳酸，在肾脏血管和小管功能的调节中起重要作用。鉴于20-HETE对肾功能的重要性，确定和表征那些控制20-HETE产生和活性的因素是重中之重，因为它们决定了类二十烷酸对肾脏作用的深度和广度。环加氧酶（COX-1和COX- 2）和一氧化氮合酶（NOS）分别被认为是调控20-HETE代谢和产生的核心。三个目标将解决COX和NO对肾脏20-HETE水平和活动的假设重要性。AIM 1建立高血压AII输注模型，确定影响20-HETE生成和生物活性的细胞因子、NO和COX（-1和-2）之间的关系和可能的相互作用。Aim 2利用高盐摄入对NO生成的相对选择性影响和低盐摄入对皮质COX-2表达的相对选择性影响，研究它们对20-HETE组织水平和皮质20-HETE代谢物生物活性谱的单独影响。AIM 3研究了糖皮质激素对TAL中COX-2表达的强大负面影响，以确定肾上腺素后TNF和COX-2（可能还有iNOS）的相互作用，并将这些因素中的一个或多个与CYP450 AA代谢的抑制和肾功能的变化联系起来。