TOXINS AND HEPATOCELLULAR PHOSPHOGLYCERIDE CATABOLISM

毒素和肝细胞磷酸甘油酯分解代谢

• 批准号: 3229875
• 负责人: ROBERT G LAMB
• 金额: $ 11.82万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-02-01 至 1991-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3229875
• 关键词: bromobenzenes; carbon tetrachloride; cell death; electron microscopy; enzyme inhibitors; enzyme mechanism; gel electrophoresis; hepatotoxin; laboratory rat; lipid biosynthesis; lipid metabolism; liver cells; liver function; liver toxic disorder; membrane activity; membrane lipids; membrane structure; microscopy; peroxidation; phosphoglycerides; phospholipase C; phospholipids; protein biosynthesis; proteolysis; radiotracer; scintillation counter; spectrometry; thin layer chromatography; tissue /cell culture; toxin metabolism; transaminases

The hepatotoxicity of carbon tetrachloride (CCl4) is primarily a result of electrophilic metabolites such as the trichloromethyl radical (.CCl3). Yet, the mechanism(s) by which .CCl3 causes cell death are still unresolved. The primary objectives of these studies are to demonstrate that: 1) membrane (endoplasmic reticulum) phospholipids such as phosphatidylcholine (PC) are critical targets of .CCl3; 2) the cytosol is a reservoir of rapidly activated (translocation) enzymes that regulate the degradation (phospholipase C) and biosynthesis (phosphocholine cytidylyltransferase) of membrane (PC); 3) the formation of membrane PC.CCl3 adducts results in rapid, enzyme (cytosolic) mediated alterations in membrane PC metabolism and content that are critical events in .CCl3- dependent liver cell death. The validity of these concepts will be established by assessing the influence of CC14 and several CC14 structural analogues (CBrCl3, CHCl3, and CFCl3) on liver cell phospholipid degradation, biosynthesis and content in vivo and in vitro. Experimental conditions will be selected which increase (phenobarbital induction) and decrease (metrypone and SKF 525A) the formation of electrophilic metabolites and chemical- dependent hepatotoxicity. These studies will increase our understanding of how reactive chemical metabolites cause liver cell injury. This information is crucial to our understanding of how to prevent and treat chemical-dependent liver cell necrosis.

四氯化碳（CCL4）的肝毒性主要是 亲电代谢物（例如三氯甲基）的结果 激进（.CCL3）。 然而，.ccl3的机制 死亡仍未解决。 这些的主要目标 研究是证明： 1）膜（内质网）磷脂，例如 磷脂酰胆碱（PC）是.ccl3的关键靶标； 2）细胞质是快速激活（易位）的储层 调节降解（磷脂酶C）和 膜的生物合成（磷脂细胞转移酶） （个人电脑）; 3）膜PC的形成。CCL3加合物迅速导致 酶PC中酶（胞质）介导的改变 代谢和内容是.ccl3-中的关键事件 依赖的肝细胞死亡。 这些概念的有效性将通过评估 CC14和几个CC14结构类似物的影响 （CBRCL3，CHCL3和CFCL3）在肝细胞磷脂上 体内和体外的降解，生物合成和含量。 将选择增加的实验条件 （苯巴比妥诱导）和减少（Metrypone和SKF 525a） 亲电代谢物和化学物质的形成 依赖性肝毒性。 这些研究将增加我们对反应性的理解 化学代谢产生肝细胞损伤。 此信息是 对于我们对如何预防和治疗的理解至关重要 化学依赖性肝细胞坏死。