Pathogenesis of carbon tetrachloride-induced hepatocyte injury bioactivation of CCl4 by cytochrome P450 and effects on lipid homeostasis

The CCl4-induced development of liver damage was studied in monolayer cultu res of primary rat hepatocytes: (1) CCl4 caused accumulation of triglycerides in hepatocytes following cyto chrome P450 induction with beta -naphthoflavone or metyrapone. Ethanol or a high dose of insulin plus triiodothyronine had the same effect. (2) CCl4 i ncreased the synthesis of fatty acids and triglycerides and the rate of lip id 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 lipi ds was decreased by almost 50% after incubation with CCl4, while saturated fatty acids increased slightly. (5) CCl4 exerted a pronounced inhibitory ef fect on the exocytosis of macromolecules (albumin), but did not affect secr etion of bile acids from hepatocytes.