CELLULAR MECHANISMS OF XENOBIOTIC TRANSPORT

异生物运输的细胞机制

• 批准号: 6162307
• 负责人: D S MILLER
• 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/6162307
• 关键词: P glycoprotein; brain metabolism; cell membrane; choroid plexus; cyclosporines; cytoskeleton; drug /agent; drug metabolism; enzyme activity; fluorescence microscopy; intracellular transport; kidney metabolism; microinjections; multidrug resistance; protein kinase C; renal tubular transport; tissue /cell culture; toxin; toxin metabolism; vesicle /vacuole; video microscopy

Summary of Work: Transporting epithelia, such as kidney, liver and choroid plexus, remove potentially toxic chemicals from the body and from protected fluid compartments, e.g., cerebrospinal fluid and aqueous humor, and thus play a major role in limiting xenobiotic action. We are using comparative models (renal proximal tubules and hepatocytes from lower vertebrates and invertebrates and mammalian cells in culture derived from kidney, choroid plexus and eye) in combination with fluorescence microscopy (conventional and confocal), video imaging, intracellular microinjection and isolated membrane vesicle techniques to define the cellular mechanisms that drive xenobiotic transport. Recent discoveries include: 1) vesicle mediated and microtubule-dependent transcellular transport of organic anions and organic cations in renal proximal tubule, liver and choroid plexus, 2) a Na-independent, excretory transport system for large organic anions in renal proximal tubule, and 3) potent uptake and efflux mechanisms for organic anions, e.g., prostaglandins, in trabecular meshwork endothelial cells from human eye. Second, we will evaluate the role of competition for excretory transport as a mechanism underlying toxic interactions between xenobiotics. In this regard, preliminary data for renal proximal tubule demonstrate 1) interactions between grapefruit juice flavonoids and drugs handled by renal p-glycoprotein, e.g., cyclosporins and Ca channel blockers, and 2) interactions between phenolphthalein-glucoronide and transporters for organic anions and p-glycoprotein substrates.

工作总结：转运上皮细胞，如肾脏、肝脏和 脉络丛，从身体和从皮肤中清除潜在的有毒化学物质。 受保护的流体隔室，例如，脑脊液和房水 幽默，因此在限制异生素作用中起主要作用。 我们 使用比较模型（肾近端小管和肝细胞， 低等脊椎动物和无脊椎动物以及培养的哺乳动物细胞 来源于肾、脉络丛和眼）与 荧光显微镜（常规和共聚焦），视频成像， 细胞内显微注射和分离膜囊泡技术， 定义了驱动异生物质运输的细胞机制。 最近 发现包括：1）囊泡介导和微管依赖 肾脏中有机阴离子和有机阳离子的跨细胞转运 近端小管，肝脏和脉络丛，2）Na非依赖性，排泄 肾近端小管中大有机阴离子的转运系统，和 3)有机阴离子的有效吸收和流出机制，例如， 人眼小梁网内皮细胞中的洋地黄素。 其次，我们将评估竞争对排泄运输的作用 作为异生物质之间毒性相互作用的潜在机制。 在 关于这一点，肾近端小管的初步数据表明：1） 葡萄柚汁黄酮类化合物和药物之间的相互作用 肾P-糖蛋白，例如，环孢菌素和Ca通道阻断剂，和2） 酚酞-葡萄糖醛酸苷和转运蛋白之间的相互作用 有机阴离子和P-糖蛋白底物。