Identification Of Mouse Cyp2c Involved In Arachidonic Ac

小鼠 Cyp2c 参与花生四烯酸的鉴定

• 批准号: 6673249
• 负责人: JOYCE GOLDSTEIN
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6673249
• 关键词: arachidonate; cytochrome P450; drug metabolism; eicosanoid metabolism; eicosanoids; enzyme activity; gene targeting; laboratory mouse; omega 3 fatty acid; retinoids; toxin metabolism; vitamin metabolism

Summary: These studies were initiated to determine the endogenous function of the CYP2Cs using the human and the mouse as a model. We have found organ-specific expression of the CYP2Cs in extrahepatic organs such as the heart muscle, endothelial cells of blood vessels, lung, kidney, adrenals, aorta, reproductive organs, white blood cells and eyes (optic nerve, rods and cones. Four potentially new CYP2Cs (CYP2C44, CYP2C50, CYP22C51 and CYP2C52p). Metabolism of arachidonic acid by the five CYPs indicated they were regio and stereospecific selective. Mouse CYP2C40 was found in relatively high amounts in colon, cecum, kidney and heart. CYP2C40 metabolizes arachidonic acid (AA) to 16R- and 16S-HETE. This is the first P450 found to produce 16-HETE as a primary product. Intestinal microsomes also produced 16-HETE. 16R-HETE is thought to be important in processes such as renal vasodilation and inhibiting neutrophil aggregation and adhesion. These initial studies indicate very organ specific expression of CYPs which produce very regio and stereospecific prodcuts of arachidonic acid. Therefore the CYP2Cs may have important physiological roles in heart, cecum, colon, endothelial cells, lung, blood vessels and eyes. This year, we identified a new CYP2C, CYP2C44, in murine kidney. CYP2C44 metabolizes arachidonic acid in a regio and stereospecific manner to 11R,12S-HETE. This EET is known to be important in vasodilation. Human CYP2C8 was found in human heart and aorta. Studies were initiated in human eyes and retinal cells. One or more CYP2Cs appear to be present in human retinal cells.

摘要：这些研究最初是以人和小鼠为模型来确定细胞色素P2磷酸酶的内源性功能。我们已经发现在肝外器官如心肌、血管内皮细胞、肺、肾、肾上腺、主动脉、生殖器官、白细胞和眼睛(视神经、视杆和视锥)中有器官特异性的表达。4个潜在的新的细胞色素P450(CYP2C44、CYP2C50、CYP22C51和CYP2C52p)。5个环糊精对花生四烯酸的代谢表明它们具有区域选择性和立体选择性。在小鼠的结肠、盲肠、肾脏和心脏中发现了较高的含量。细胞色素P450将花生四烯酸(AA)代谢成16R-和16S-HETE。这是第一个发现以16-HETE为主要产物的P450。肠道微生物体也产生了16-HETE。16R-HETE被认为在肾血管扩张、抑制中性粒细胞聚集和黏附等过程中起重要作用。这些初步研究表明，Cyps的表达具有器官特异性，可以产生非常区域性和立体特异性的花生四烯酸产物。因此，在心脏、盲肠、结肠、血管内皮细胞、肺、血管和眼等组织中，细胞色素P450-2Cs可能具有重要的生理作用。今年，我们在小鼠肾脏中发现了一种新的细胞色素P450 2 C，即细胞色素P450 2 C44。CYP2C44以区域和立体特异性的方式将花生四烯酸代谢为11R，12S-HETE。已知这种EET在血管扩张中很重要。在人的心脏和主动脉中发现了人的细胞色素P450 2 C8。研究是在人眼和视网膜细胞上开始的。人类视网膜细胞中似乎存在一个或多个细胞色素P2+2 C。