MECHANISM OF CARBON TETRACHLORIDE HEPATOTOXICITY

四氯化碳肝毒性机制

基本信息

批准号：
3224980
负责人：
JOSE A CASTRO
金额：
$ 4.12万
依托单位：
INSTITUTO DE INVESTIGACIONES CIENTIFICAS
依托单位国家：
美国
项目类别：
财政年份：
1979
资助国家：
美国
起止时间：
1979-01-01 至 1994-06-30
项目状态：
已结题

项目摘要

The broad long term objectives of the project are to contribute to the knowledge about how chemicals cause cell injury by studying the model system CC14 hepatotoxicity. That objective includes the attempt to develop treatments based on the knowledge gained. The present project specific aims is to challenge the working hypothesis that CC14- induced liver necrosis might be related to damage to Ca++ pumps to lead to alterations in Ca++ homeostasis which might enhance phospholipid/protein/DNA degradative processes to cause cell injury. Experiments planed to be made include: 1) Studies on the role of .CC1 covalent binding (CB) and of lipid peroxidation (LP) in the "in vivo" damage by CC14 to endoplasmic reticulum, mitochondrial and nuclear Ca++ pumps. Specific inhibitors of either CB or LP are going to be used to discriminate CB or LP contribution. Use of agents potentially able to revert damage caused by LP or .CC13-mediated H abstraction from Ca++ pumps would also be made to attempt prevention of damage to them and on CC14-induced liver necrosis; 2) The potential preventive effects of Ca++ chelators and on non-phenothiazinic anticalmodulin drugs would be tested as late preventive agents against CC14-induced liver necrosis; 3) The potential preventive effects of specific and potent inhibitors of proteases, phospholipase A2 and endonuclease are going to be tested as late preventive agents against CC14- induced liver necrosis. To achieve these goals we plan to perform the necessary studies evidencing that treatments reached liver tissue (GLC; HPLC; spectrophotometry) and/or performed their expected effects (eg. inhibited CB or LP; reverted damage to Ca++ pumps; prevented protein/phospholipid/DNA degradation; prevented damage as observable by histology, electron microscopy and blood increases in isocitric acid dehydrogenase) and that preventive effects can not be attributable to actions on other parameters influencing the course of CC14-induced liver damage of non-specific nature (CC14 levels in liver, body temperature).4 The major health implication of the project is the potential development of treatments of general value able to operate at late stages of poisoning by CC14 and other chemicals not previously amenable to modulation and potentially useful to many pathologies where changes in calcium homeostasis and enhancement of degradative processes might be relevant.

该项目的广泛长期目标是促进通过研究模型了解化学物质如何导致细胞损伤系统CC14肝毒性。该目标包括尝试开发根据所获得的知识进行治疗。本项目具体目的是挑战 CC14 诱导肝脏的工作假设坏死可能与 Ca++ 泵的损伤有关，从而导致 Ca++ 稳态可能会增强磷脂/蛋白质/DNA 降解导致细胞损伤的过程。计划进行的实验包括：1) .CC1 共价结合 (CB) 和脂质过氧化作用的研究 (LP) CC14 对内质网的“体内”损伤，线粒体和核 Ca++ 泵。 CB 或 CB 的特异性抑制剂 LP 将被用来歧视 CB 或 LP 的贡献。使用可能能够恢复 LP 或 .CC13 介导的 H 造成的损害的药剂还可以从 Ca++ 泵中提取，以尝试预防对它们的损害以及CC14诱导的肝坏死； 2）潜力 Ca++ 螯合剂和非吩噻嗪类药物的预防作用抗调节蛋白药物将作为晚期预防剂进行测试 CC14诱导的肝坏死； 3）潜在的预防作用蛋白酶、磷脂酶 A2 和的特异性和有效抑制剂核酸内切酶将作为 CC14-的晚期预防剂进行测试诱发肝坏死。为了实现这些目标，我们计划执行必要的研究证明治疗已到达肝组织（GLC；高效液相色谱法；分光光度法）和/或执行其预期效果（例如。抑制CB或LP；恢复了 Ca++ 泵的损坏；阻止蛋白质/磷脂/DNA降解；防止了可观察到的损害组织学、电子显微镜和血液中异柠檬酸增加脱氢酶）并且预防效果不能归因于对影响 CC14 诱导肝脏进程的其他参数的作用非特异性损害（肝脏中的 CC14 水平、体温）。4 该项目对健康的主要影响是潜在的发展具有普遍价值的治疗方法能够在中毒后期发挥作用 CC14 和其他化学品以前不适合调制和对钙稳态变化的许多病理学可能有用和增强降解过程可能是相关的。