Mouse Cyp2c Involved In Arachidonic Acid

小鼠 Cyp2c 参与花生四烯酸

• 批准号: 6504701
• 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/6504701
• 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.

总结：启动这些研究的目的是使用人和小鼠作为模型测定CYP 2C的内源性功能。我们已经发现CYP 2C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、白色血细胞和眼睛（视神经、视杆和视锥）中的器官特异性表达。4种潜在的新CYP 2C（CYP 2C 44、CYP 2C 50、CYP 22 C51和CYP 2C 52 p）。5种CYP对花生四烯酸的代谢具有区域和立体选择性。 在小鼠结肠、盲肠、肾脏和心脏中发现相对较高的CYP 2C 40。CYP 2C 40将花生四烯酸（AA）代谢为16 R-和16 S-HETE。这是发现的第一个产生16-HETE作为主要产物的P450。肠微粒体也产生16-HETE。16 R-HETE被认为在诸如肾血管舒张和抑制中性粒细胞聚集和粘附的过程中是重要的。这些初步的研究表明，CYP的表达具有器官特异性，它产生花生四烯酸的区域和立体特异性产物。因此，CYP 2C可能在心脏、盲肠、结肠、内皮细胞、肺、血管和眼睛中具有重要的生理作用。今年，我们在小鼠肾脏中鉴定了一种新的CYP 2C，CYP 2C 44。CYP 2C 44以区域和立体特异性方式将花生四烯酸代谢为11 R，12 S-HETE。已知EET在血管舒张中很重要。人CYP 2C 8存在于人心脏和主动脉中。研究开始于人眼和视网膜细胞。一种或多种CYP 2C似乎存在于人视网膜细胞中。