MECHANISM OF CARBON TETRACHLORIDE HEPATOTOXICITY

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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.