TARGETED DELIVERY OF GLUTATHIONE PRECURSOR TO THE LIVER

谷胱甘肽前体定向输送至肝脏

• 批准号: 2182743
• 负责人: JEANETTE C ROBERTS
• 金额: $ 9.82万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-02-01 至 1997-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2182743
• 关键词: acetaminophen; aminoacid analog; aminoacid metabolism; carbohydrate receptor; cysteine; cytochrome P450; detoxification; disaccharides; drug design /synthesis /production; glutathione; hepatotoxin; laboratory mouse; liver metabolism; overdose; prodrugs; toxin metabolism

The human organism is quite adept at handling potentially harmful xenobiotic substances, such as drugs, environmental pollutants and food contaminants, that have been ingested, inhaled or absorbed either actively or passively. While many organs and tissues contribute to the detoxication process, the liver is the major site of metabolism, where foreign materials are detoxified before normal biochemical processes are disrupted. Metabolism cannot be equated with detoxication in all cases, however. Many xenobiotic substances are metabolically transformed into compounds that are more toxic than the original substance. Since these metabolic processes are prevalent in the liver, this organ is particularly subject to the toxicity of such bioactivated intermediates. The proposed research will investigate novel therapeutic routes to alleviate the hepatotoxicity associated with high doses of the common analgesic agent, acetaminophen. Acetaminophen overdose depletes hepatic glutathione (GSH) and allows damage to normal cellular constituents. Supplying L-cysteine, one of the amino acid precursors of GSH, stimulates GSH biosynthesis and amplifies the existing protective mechanism. New prodrug forms of this amino acid, synthesized with disaccharide components, are proposed that allow selective delivery to the liver by capitalizing on the high level of carbohydrate receptors in this organ. Numerous parameters will be investigated to determine the biochemical basis for the efficacy of the prodrugs. Hepatic localization and the fate of the administered prodrugs will be studied using radio-labeled compounds. Hepatic levels of important thiols will be determined after the administration of the prodrugs. The activities of enzymes involved in GSH synthesis and metabolism may be important and will be investigated, as will the content of cytochrome P-450. All of these parameters will be studied both in the absence and the presence of acetaminophen to assess the prodrugs potential when the toxic insult is present. Protection by the prodrugs against the potent hepatotoxicity of acetaminophen will be determined in vivo. These studies offer the possibility of improving the management of acetaminophen overdose, which is a clinically relevant situation. The proposed research will provide important insight into the precesses of GSH regulation and may provide new agents with therapeutic utility.

人体有机体非常善于处理潜在的有害物质 外源物质，例如药物、环境污染物和食物 已被摄入、吸入或主动吸收的污染物 或被动地。 虽然许多器官和组织有助于解毒 在此过程中，肝脏是代谢的主要场所，异物在这里 在正常的生化过程被破坏之前被解毒。 然而，新陈代谢并不在所有情况下都等同于解毒。 许多 外源物质通过代谢转化为化合物 比原来的物质毒性更大。 由于这些代谢过程 普遍存在于肝脏中，该器官特别容易受到 此类生物活性中间体的毒性。 拟议的研究将 研究减轻肝毒性的新治疗途径 与高剂量的常见镇痛剂对乙酰氨基酚有关。 对乙酰氨基酚过量会消耗肝脏谷胱甘肽 (GSH) 并造成损害 到正常的细胞成分。 供应L-半胱氨酸，氨基酸之一 GSH 的酸性前体，刺激 GSH 生物合成并放大 现有的保护机制。 这种氨基酸的新前药形式， 由二糖成分合成，建议允许选择性 利用高水平的碳水化合物输送到肝脏 该器官中的受体。 将研究许多参数 确定前药功效的生化基础。 肝的 将研究所施用前药的定位和命运 使用放射性标记的化合物。 重要硫醇的肝脏水平将 在施用前药后测定。 的活动 参与 GSH 合成和代谢的酶可能很重要，并且会 以及细胞色素 P-450 的含量。 所有这些 将在不存在和存在的情况下研究参数 对乙酰氨基酚评估毒性损伤时前药的潜力 展示。 前药对强效肝毒性的保护作用 对乙酰氨基酚将在体内测定。 这些研究为改善管理提供了可能性 对乙酰氨基酚过量，这是一种临床相关情况。 这 拟议的研究将为 GSH 的过程提供重要的见解 调节并可能提供具有治疗用途的新药物。