Phospholipids are essential structural and functional components of hepatocellular membranes. Therefore, a bromobenzene (BB)- and CCl4-dependent reduction in the steady-state (equilibrium between production and degradation) level of hepatocellular phospholipids may represent a critical event in BB- and CCl4-induced hepatocyte injury. The primary objective of this project is to determine if4BB- and CCl4-dependent liver cell injury and death are related to the alterations that exposure to these agents in vivo and in vitro produce in the content of hepatocellular phospholipids. This goal will be achieved by exposing hepatocyte monolayers and intact animals (rats) to BB and CCl4 and correlating changes in the degfradation, formation and content of membrane phospho lipids with the functional (release of intracellular K plus and aminotransferase enzymes, etc.) and structural (morphological changes assessed by light and electron microscopy) integrity of hepatocytes and hepatocellular membranes. Hopefully, these studies will establish that: 1) a rapid (1 min), Ca2+-dependent, BB- and CCl4-induced rise in a phospholipase C mediated reduction in hepatocellular phospholipids represents a key event in hepatotoxin-induced hepatocyte injury; 2) the severity (reversible or irreversible) of BB- and CCl4-dependent hepatocyte damage is directly related to the degree of hepatocellular phospholipid degradation and the ability of cells to synthesize new phospholipids (repair injured membranes). These studies will also increase our knowledge of those factors that regulate hepatocellular phospholipid degradation, biosynthesis and content and this information may be fundamentally important in understanding the pathogenesis of hepatotoxin-induced liver cell injury and death.
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