IN VIVO F-19 NMR STUDIES OF THE METABOLISM OF FLUROINATED ANESTHETICS

含氟麻醉剂代谢的体内 F-19 NMR 研究

• 批准号: 3898110
• 负责人: R E LONDON
• 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/3898110
• 关键词: aminoacid oxidase; anesthetics; drug adverse effect; fluorine; halothane; inhalation anesthesia; methionine; methoxyflurane; nuclear magnetic resonance spectroscopy; oxidation reduction reaction; sarcosine; toxin metabolism; tritium

The liver is the principal organ involved in the detoxification of a broad range of xenobiotics. During the past decade, it has become possible to monitor the metabolism of organs non-invasively in anesthetized animals and humans using surface coil NMR probes which can be placed directly over the tissue of interest. Using this technique, the metabolic transformations of xenobiotics can, in favorable cases, be directly observed, and perturbations of cellular energy metabolism and redox chemistry can also be studied. Using this technique, we have carried out studies of metabolism of several fluorinated inhalation anesthetics in order to obtain a better understanding of the basis for the toxic side effects which accompany the use of many of these compounds. These studies ave provided the first unequivocal identification of methoxydifluoroacetate as a metabolite of the anesthetic methoxyflurane. Additionally, we have adapted this technique to the study of transmethylation reactions based on direct observations by deuterium NMR of (methyl-2H3)methionine. It was found that excess methionine s metabolized largely via the initial transfer of the methyl group to glycine to yield N-methylglycine (sarcosine), which is subsequently processed in the mitochondrion. The activity of this glycine/sarcosine shuttle is subject to interference by a number of chemicals including the methionine analog ethionine, as well as sodium benzoate. Studies with deuterated D-methionine indicate that his analog is metabolized via initial oxidative deamination by D-amino acid oxidase, then transaminated to yield L-methionine which is the metabolized via glycine N-methyltransferase.

肝脏是参与解毒的主要器官。 种类繁多的外源生物。在过去的十年里，它 无创监测器官新陈代谢成为可能 在麻醉动物和人类中使用表面线圈核磁共振探针 它可以直接放置在感兴趣的组织上。vbl.使用 这项技术，外源生物的代谢转化可以， 在有利的情况下，可以直接观察到，并且 还可以研究细胞的能量代谢和氧化还原化学。 利用这项技术，我们已经进行了代谢的研究 几种含氟吸入麻醉剂，以获得 更好地了解毒副作用的基础 伴随着许多这类化合物的使用。这些研究都是 提供了第一个明确的身份证明 甲氧基二氟乙酸酯作为麻醉剂的代谢物 甲氧基氟烷。此外，我们还将这项技术应用于 基于DIRECT的转甲基化反应研究 (甲基-2H3)蛋氨酸的氢核磁共振观察确实是 研究发现，S体内过量的蛋氨酸主要是通过最初的 将甲基转移到甘氨酸生成N-甲基甘氨酸 (肌氨酸)，随后在线粒体中进行处理。 这种甘氨酸/肌氨酸穿梭的活性受 包括蛋氨酸在内的多种化学物质的干扰 类似的乙硫氨酸，以及苯甲酸钠。研究对象： 氢化D-蛋氨酸表明他的类似物是通过 先用D-氨基酸氧化物酶进行氧化脱氨，然后 转氨酶生成L-蛋氨酸，通过 甘氨酸N-甲基转移酶。