The role of phospholipid metabolism in bromobenzene- and carbon tetrachloride-dependent hepatocyte injury.
Sprague-Dawley rats and cultured rat hepatocytes exposed to bromobenzene (BB) and carbon tetrachloride (CCl4) display rapid and significant increases and decreases in hepatic phospholipase C (PLC) and sn-glycerol-3-phosphate acyltransferase (GPAT) activities, respectively. Primary cultures of adult rat hepatocytes were used to determine if the BB- and CCl4-dependent alterations in phospholipid metabolism were related to the hepatotoxicity of these agents. Cultured hepatocytes exposed to BB and CCl4 exhibited a rapid (1 to 5 min). PLC-mediated reduction (20 to 80%) in [32P]phosphatidylserine content. Other phospholipids were also reduced; however, phosphatidylserine was preferentially degraded by hepatotoxin-activated PLC. A time course of CCl4-and BB-induced cellular events showed that these agents (1) rapidly activate liver cell PLC activity; (2) accelerate 86Rb release; (3) decrease GPAT acyltransferase activity; and (4) cause a release of intracellular enzymes (GOT and GPT). All of these BB- and CCl4-mediated effects on the functional integrity of liver cells were blocked or reduced by agents (EDTA and chlorpromazine) that reduce the BB- and CCl4-dependent rise in PLC activity. Therefore, BB- and CCl4-dependent alterations in the functional and structural integrity of liver cells may be a result of accelerated phospholipid degradation and a corresponding inability of the cell to repair injured membranes by generating new phospholipids.
D000818:Animals; D001969:Bromobenzenes / Q000633:toxicity*; D002118:Calcium / Q000502:physiology; D002251:Carbon Tetrachloride / Q000633:toxicity*; D005992:Glycerol-3-Phosphate O-Acyltransferase / Q000032:analysis; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010718:Phosphatidylserines / Q000032:analysis; D010743:Phospholipids / Q000378:metabolism*; D011868:Radioisotopes; D051381:Rats; D011919:Rats, Inbred Strains; D012413:Rubidium / Q000378:metabolism; D010738:Type C Phospholipases / Q000032:analysis
D001969:Bromobenzenes; D010718:Phosphatidylserines; D010743:Phospholipids; D011868:Radioisotopes; D002251:Carbon Tetrachloride; D005992:Glycerol-3-Phosphate O-Acyltransferase; D010738:Type C Phospholipases; D012413:Rubidium; D002118:Calcium