Pathogenesis of carbon tetrachloride-induced hepatocyte injury bioactivation of CCI4 by cytochrome P450 and effects on lipid homeostasis.
The CCl4-induced development of liver damage was studied in monolayer cultures of primary rat hepatocytes: (1) CCl4 caused accumulation of triglycerides in hepatocytes following cytochrome P450 induction with beta-naphthoflavone or metyrapone. Ethanol or a high dose of insulin plus triiodothyronine had the same effect. (2) CCl4 increased the synthesis of fatty acids and triglycerides and the rate of lipid esterification. Cholesterol and phospholipid synthesis from acetate was also increased. (3) CCl4 reduced beta-oxidation of fatty acids as assessed by CO2-release and ketone body formation. Hydrolysis of triglycerides was also reduced. (4) The content of unsaturated fatty acids in microsomal lipids was decreased by almost 50% after incubation with CCl4, while saturated fatty acids increased slightly. (5) CCl4 exerted a pronounced inhibitory effect on the exocytosis of macromolecules (albumin), but did not affect secretion of bile acids from hepatocytes.
Boll
M
M
Institute of Toxicology, GSF--National Research Center for Environment and Health, München, Bundesrepublik Deutschland.
Weber
L W
LW
Becker
E
E
Stampfl
A
A
D015660:7-Alkoxycoumarin O-Dealkylase / Q000378:metabolism; D000818:Animals; D001711:Biotransformation; D002251:Carbon Tetrachloride / Q000493:pharmacokinetics / Q000633:toxicity*; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism*; D004790:Enzyme Induction; D000431:Ethanol / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006706:Homeostasis; D007328:Insulin / Q000494:pharmacology; D007700:Kinetics; D050356:Lipid Metabolism; D008099:Liver / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D008797:Metyrapone / Q000494:pharmacology; D010743:Phospholipids / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014280:Triglycerides / Q000378:metabolism; D014284:Triiodothyronine / Q000494:pharmacology; D019324:beta-Naphthoflavone / Q000494:pharmacology
D005227:Fatty Acids; D007328:Insulin; D010743:Phospholipids; D014280:Triglycerides; D014284:Triiodothyronine; D000431:Ethanol; D019324:beta-Naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D002251:Carbon Tetrachloride; D015660:7-Alkoxycoumarin O-Dealkylase; D008797:Metyrapone