1. Addition of CCl4 to suspensions of reduced liver microsomes produces a difference spectrum with max. absorption at 454 nm. This absorption develops within approx. 5 min (37°).2. Dehalogenation of CCl4 to CHCl3 by NADPH reduced liver microsomes displays similar kinetics.3. The irreversible binding of 14CCl4 to microsomal proteins proceeds more slowly than CHCl3 formation.4. The first step in CCl4 liver toxicity is the very rapid formation of fast reacting intermediates. This step might occur between the binding of CCl4 to cytochrome P-450 and the release of CHCl3. The primary intermediates bind to liver lipids and proteins and also initiate lipid peroxidation.

Binding of 14C-Carbon Tetrachloride to Microsomal Proteins in vitro and Formation of CHCl3 by Reduced Liver Microsomes

Effect of clofibrate on the handling of dietary and liver fat.

Serum and hepatic cholesterol content in rats treated with polychlorinated biphenyls (PCBs, KC-400) were increased compared to those of control rats. This increase of cholesterol content was reduced to control level by simultaneous administration of ethyl p-chlorophenoxyisobutyrate (CPIB). Also, when lecithin-cholesterol acyltransferase (LCAT) (EC. 2.3.1.43) activity was expressed as the net cholesterol esterification, the acyltransferase activity in rats treated with PCBs was elevated, while the elevated acyltransferase activity was brought to control level by simultaneous administration of CPIB. On the other hand, the amount of bile of rats treated with CPIB, PCBs and PCBs-CPIB was increased, but free and total cholesterol content in bile of these treated rats was decreased to 40–60% of those of control rats. Moreover, cytochrome P-450 content in liver microsomes of rats treated with CPIB, PCBs and PCBs-CPIB was increased. At the same time, cholesterol-metabolizing activity in liver microsomes of rats treated with CPIB, PCBs and PCBs-CPIB also was elevated. Similar results were obtained for drug metabolizing (aniline hydroxylation and aminopyrine N-demethylation) activity. In addition, the amount of bile acids excreted from rats treated with CPIB, PCBs and PCBs-CPIB was increased compared to that of control rats. These results suggest that hypercholesterolemia induced by oral ingestion of PCBs is recovered by CPIB treatment and that this hypocholesterolemic effect of CPIB may be related partly to the elevation of hepatic mixed function oxidase activity for cholesterol catabolism.

D. Giorgini

Papers

The effect of α-methyl γ-phenyl butyric acid on sterol biosynthesis in vitro