The hepatotoxicity of carbon tetrachloride (CCl4) is primarily a result of electrophilic metabolites such as the trichloromethyl radical (.CCl3). Yet, the mechanism(s) by which .CCl3 causes cell death are still unresolved. The primary objectives of these studies are to demonstrate that: 1) membrane (endoplasmic reticulum) phospholipids such as phosphatidylcholine (PC) are critical targets of .CCl3; 2) the cytosol is a reservoir of rapidly activated (translocation) enzymes that regulate the degradation (phospholipase C) and biosynthesis (phosphocholine cytidylyltransferase) of membrane (PC); 3) the formation of membrane PC.CCl3 adducts results in rapid, enzyme (cytosolic) mediated alterations in membrane PC metabolism and content that are critical events in .CCl3- dependent liver cell death. The validity of these concepts will be established by assessing the influence of CC14 and several CC14 structural analogues (CBrCl3, CHCl3, and CFCl3) on liver cell phospholipid degradation, biosynthesis and content in vivo and in vitro. Experimental conditions will be selected which increase (phenobarbital induction) and decrease (metrypone and SKF 525A) the formation of electrophilic metabolites and chemical- dependent hepatotoxicity. These studies will increase our understanding of how reactive chemical metabolites cause liver cell injury. This information is crucial to our understanding of how to prevent and treat chemical-dependent liver cell necrosis.
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