MECHANISM OF CARBON TETRACHLORIDE HEPATOTOXICITY

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We plan to continue with our studies on the relative importance of the covalent binding of carbon tetrachloride reactive metabolites and lipid peroxidation in carbon tetrachloride-induced liver injury. We also plan to continue with studies directed to understand how cellular alterations initiated by carbon tetrachloride at the cytochrome P-450 site in the endoplasmic reticulum propagate to other cell organelles like the Golgi apparatus, plasma membrane, and the cytoplasm. We plan to perform studies directed to understand the mechanism by which disruption of calcium homeostasis during carbon tetrachloride poisoning initiates the chain of events ending in liver cell necrosis. We plan to further explore the possible role of processes of synthesis and degradation of cellular constituents in carbon tetrachloride-induced liver necrosis. Particular emphasis in protein and phospholipid degradation is going to be made. A major area of research effort in our project, is going to be the development of treatment/antidotes preventing liver cell necrosis, based on our studies on the mechanism of carbon tetrachloride-induced liver injury. We plan to explore the possibility that insights gained from the studies on cell injury by the model hepatotoxin carbon tetrachloride allowed prevention of liver cell necrosis by other hepatotoxins and cell necrosis produced by other chemicals acting in other organs like pancreas, small intestine, kidney or testes. Health implications of this project are critical, since the aim of our research is to understand how cells die after chemical or other insult and how that understanding can be used to develop treatments.