1. When clofibrate [ethyl 2-(4-chlorophenoxy)-2-methylpropionate] was administered subcutaneously to rats (600mg/kg per day for 5 days), the concentration of CoA and its acyl derivatives increased in several tissues. The increase in total CoA was 3.2-fold in the liver, 1.8-fold in the kidney, 2.7-fold in the heart and 2.4-fold in skeletal muscle. 2. To study the mechanism of this phenomenon, clofibrate-treated rats were injected with [(3)H]pantothenate intracardially and killed after 15min, 30min, 1 and 2h and 1, 3, 5 and 7 days for the determination of the incorporation of radioactivity into CoA and its precursors. Incorporation into CoA after 2h was 6.2-fold in the liver as compared with the control values and 4.6-fold in the kidneys. 3. The disappearance of the label from CoA was very slow compared with the rate of incorporation; it exhibited exponential kinetics, and was slower in the livers of the clofibrate-treated rats (t((1/2)) 18.2 days) than in the controls (t((1/2)) 5.6 days). 4. The rate of CoA degradation, calculated from the calculated rate constants of the apparent first-order kinetics of the disappearance of the label and from the CoA pool sizes, was approximately the same in the clofibrate-treated animals (11.5pmol/min per g), and the controls (11.6pmol/min per g). 5. These rates of CoA degradation indicate that the effect of clofibrate on CoA concentration may be mainly due to inhibition of the enzymes of CoA degradation, although recycling of the label cannot be excluded. The increase in the rate of pantothenate incorporation into CoA suggests that clofibrate also increases the synthesis of CoA.
The oxygen dependence of hepatic cellular respiration was studied by employing simultaneous organ spectrophotometry of cytochromes and hemoglobin, the latter used as an intrasinusoidal optical oxygen probe. The Km of cytochrome aa3 for oxygen was found to be 6.8 microM in the isolated perfused liver and 0.3 microM in suspensions of isolated hepatocytes. The results indicate that the sinusoid-to-cell pO2 gradient is about 5 torr. Optical determination of the average effective pO2 indicates that the axial sinusoidal O2 profile does not conform to zero-order O2 uptake in the liver. Because of extensive NAD+ reduction, ethanol increases the thermodynamic driving force of oxidative phosphorylation, and it also increased the oxygen consumption in both the perfused liver and the hepatocyte suspension, but had no effect on the grade of steady-state cytochrome aa3 reduction, the cellular energy state [ATP]/[ADP].[Pi], or the Km of cytochrome aa3 for oxygen. The results indicate that hepatic energy metabolism is oxygen independent at very low O2 concentrations, but that the sinusoidal axial O2 concentration is anomalous, probably due to the spatial arrangement of the metabolizing systems.
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