MECHANISM OF CARBON TETRACHLORIDE HEPATOTOXICITY

四氯化碳肝毒性机制

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/3224980
• 关键词: antidotes; atomic absorption spectrometry; calcium; calcium channel blockers; calcium flux; carbon tetrachloride; chelating agents; covalent bond; cytolysis; drug screening /evaluation; electron microscopy; endonuclease; endopeptidases; endoplasmic reticulum; enzyme inhibitors; enzyme mechanism; gas chromatography; glutathione; hepatotoxin; high performance liquid chromatography; laboratory rat; liver disorder chemotherapy; liver toxic disorder; membrane transport proteins; mitochondria; necrosis; peroxidation; phospholipase A2; phospholipids; protein degradation

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.

本项目的长远目标是为

项目成果

Species differences in the interaction between CCl4 reactive metabolites and liver DNA or nuclear protein fractions.

CCl4 反应性代谢物与肝脏 DNA 或核蛋白组分之间相互作用的物种差异。

• DOI: 10.1093/carcin/10.2.289
• 发表时间: 1989
• 期刊: Carcinogenesis
• 影响因子: 4.7
• 作者: Castro,GD;DíazGómez,MI;Castro,JA
• 通讯作者: Castro,JA

Trifluopromazine late preventive effects on carbon tetrachloride-induced liver necrosis.

三氟丙嗪对四氯化碳所致肝坏死的后期预防作用。

• DOI: 10.1006/exmp.1995.1009
• 发表时间: 1995
• 期刊: Experimental and molecular pathology.
• 作者: deFerreyra,EC;Bernacchi,AS;SanMartin,MF;Castro,GD;Castro,JA
• 通讯作者: Castro,JA

Dithiothreitol tetraacetate S-acetyl esterase activity in blood and in different tissues of male rats.

雄性大鼠血液和不同组织中的二硫苏糖醇四乙酸S-乙酰酯酶活性。

• 发表时间: 1993
• 期刊: Archives internationales de pharmacodynamie et de therapie
• 作者: deMecca,MM;Castro,GD;Castro,JA
• 通讯作者: Castro,JA

Late preventive effects against carbon tetrachloride-induced liver necrosis of the calcium chelating agent Calcion.

钙螯合剂Calcion对四氯化碳引起的肝坏死的后期预防作用。

• DOI: 10.1007/bf00316447
• 发表时间: 1989
• 期刊: Archives of toxicology
• 影响因子: 6.1
• 作者: deFerreyra,EC;Villarruel,MC;Bernacchi,AS;Fernández,G;deFenos,OM;Castro,JA
• 通讯作者: Castro,JA

N-acetyl cysteine is an early but also a late preventive agent against carbon tetrachloride-induced liver necrosis.

N-乙酰半胱氨酸是四氯化碳引起的肝坏死的早期和晚期预防剂。

• DOI: 10.1016/0378-4274(94)90202-x
• 发表时间: 1994
• 期刊: Toxicology letters
• 影响因子: 3.5
• 作者: Valles,EG;deCastro,CR;Castro,JA
• 通讯作者: Castro,JA