MECHANISM OF CARBON TETRACHLORIDE HEPATOTOXICITY

该项目的广泛的长期目标是促进 通过研究模型了解化学物质如何导致细胞损伤 系统CC 14肝毒性。 这一目标包括努力发展 根据获得的知识进行治疗。 本项目具体 目的是挑战CC 14诱导的肝脏 坏死可能与Ca++泵的损伤有关，从而导致 Ca++稳态可能增强磷脂/蛋白质/DNA降解 导致细胞损伤。 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CC 14对内质网的“体内”损伤中， 线粒体和核Ca++泵。 CB或 LP将用于区分CB或LP贡献。 使用 可能能够逆转由LP或CC 13介导的H 也可以从Ca++泵中提取，以试图防止 对它们的损害和对CC 14诱导的肝坏死的影响; 2） 钙离子螯合剂和非吩噻嗪类药物的预防作用 抗钙调素药物将作为晚期预防剂进行测试， CC 14诱导的肝坏死; 3） 蛋白酶、磷脂酶A2和 核酸内切酶将作为针对CC 14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 证明治疗到达肝组织的必要研究（GLC; HPLC;分光光度法）和/或执行其预期效果（例如， 抑制CB或LP;恢复对Ca++泵的损害;预防 蛋白质/磷脂/DNA降解;通过观察防止损伤 组织学、电子显微镜检查和异柠檬酸血液增加 脱氢酶）和预防作用不能归因于 对影响CC 14诱导的肝脏过程的其他参数的作用 非特异性损害（肝脏中的CC 14水平、体温）。 该项目的主要健康影响是潜在的发展， 具有一般价值的治疗方法，能够在中毒晚期发挥作用， CC 14和其他以前不适合调节的化学品， 可能适用于许多病理学，其中钙稳态的变化 和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.