MECHANISM OF CARBON TETRACHLORIDE HEPATOTOXICITY

该项目广泛的长期目标是为 通过研究模型了解化学物质如何引起细胞损伤 系统CC14肝毒性。这一目标包括试图发展 根据所获得的知识进行治疗。本项目具体情况 目的是挑战CC14诱导肝脏的工作假说 坏死可能与钙泵受损导致血管紧张素转换酶改变有关。 钙离子动态平衡可能促进磷脂/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)在CC14对内质网的“体内”损伤中， 线粒体和细胞核的钙泵。CB或CB的特定抑制剂 LP将被用来区分CB或LP的贡献。使用 潜在能够恢复LP或.CC13介导的H造成的损害的代理 还将从钙泵中提取，以尝试预防 对它们和CC14诱导的肝坏死的损害；2)潜在的 钙离子螯合剂对非吩噻嗪中毒的预防作用 抗钙调素药物将作为晚期预防药物进行测试 CC14诱导的肝坏死；3)潜在的预防作用 特异性和强效的蛋白水解酶抑制剂，磷脂酶A2和 内切酶将作为CC14的晚期防御剂进行测试- 致肝坏死。为了实现这些目标，我们计划实施 证明治疗到达肝组织的必要研究(GLC； 高效液相色谱；分光光度法)和/或实现其预期效果(例如， 抑制CB或LP；恢复对Ca++泵的损害；防止 蛋白质/磷脂/DNA降解；可观察到的防止损害 组织学、电子显微镜和血液中异柠檬酸含量增加 脱氢酶)，而预防效果不能归因于 影响CC14诱导大鼠肝脏病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 能够在中毒后期操作的一般价值的治疗方法 CC14和其他以前不受调制和控制的化学品 可能对钙稳态改变的许多病理有用 而加强降解过程可能是相关的。

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.