MECHANISM OF CARBON TETRACHLORIDE HEPATOTOXICITY

四氯化碳肝毒性机制

• 批准号: 3224978
• 负责人: JOSE A CASTRO
• 金额: $ 7.15万
• 依托单位: NAVAL INSTITUTE OF SCI & TECH RESEARCH
• 依托单位国家: 美国
• 财政年份: 1979
• 资助国家: 美国
• 起止时间: 1979-01-01 至 1990-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3224978
• 关键词: DNA; RNA; antidotes; carbon tetrachloride poisoning; cell death; chemical carcinogen; cytochrome P450; electron microscopy; endoplasmic reticulum; fatty liver; free radicals; gas chromatography; lipid peroxides; liver cirrhosis; liver neoplasms; liver toxic disorder; peroxidation; polysomes; radiotracer

We plan to continue with our studies on the relative importance of the covalent binding of carbon tetrachloride reactive metabolites and lipid peroxidation in carbon tetrachloride-induced liver injury. We also plan to continue with studies directed to understand how cellular alterations initiated by carbon tetrachloride at the cytochrome P-450 site in the endoplasmic reticulum propagate to other cell organelles like the Golgi apparatus, plasma membrane, and the cytoplasm. We plan to perform studies directed to understand the mechanism by which disruption of calcium homeostasis during carbon tetrachloride poisoning initiates the chain of events ending in liver cell necrosis. We plan to further explore the possible role of processes of synthesis and degradation of cellular constituents in carbon tetrachloride-induced liver necrosis. Particular emphasis in protein and phospholipid degradation is going to be made. A major area of research effort in our project, is going to be the development of treatment/antidotes preventing liver cell necrosis, based on our studies on the mechanism of carbon tetrachloride-induced liver injury. We plan to explore the possibility that insights gained from the studies on cell injury by the model hepatotoxin carbon tetrachloride allowed prevention of liver cell necrosis by other hepatotoxins and cell necrosis produced by other chemicals acting in other organs like pancreas, small intestine, kidney or testes. Health implications of this project are critical, since the aim of our research is to understand how cells die after chemical or other insult and how that understanding can be used to develop treatments.

我们计划继续研究 四氯化碳反应性代谢物与脂质的共价结合 四氯化碳引起的肝损伤中的过氧化作用。 我们还计划继续开展旨在了解细胞如何 四氯化碳在细胞色素 P-450 位点引发的改变 在内质网中传播到其他细胞器，例如 高尔基体、质膜和细胞质。 我们计划进行旨在了解其机制的研究 四氯化碳中毒期间钙稳态的破坏 引发一系列事件，最终导致肝细胞坏死。 我们计划进一步探索合成过程的可能作用 四氯化碳诱导的肝脏中细胞成分的降解 坏死。 特别强调蛋白质和磷脂的降解 将被制作。 我们项目的一个主要研究领域是 开发预防肝细胞坏死的治疗/解毒剂 我们对四氯化碳所致肝损伤机制的研究。 我们计划探索从研究中获得的见解的可能性 允许模型肝毒素四氯化碳损伤细胞 预防其他肝毒素引起的肝细胞坏死和细胞坏死 由作用于其他器官（如胰腺、小器官）的其他化学物质产生 肠、肾或睾丸。 该项目对健康的影响至关重要，因为我们的目标是 研究的目的是了解细胞在化学或其他损伤后如何死亡 如何利用这种理解来开发治疗方法。