Inhibition of mixed-function oxidation in perfused rat liver by fluoroacetate treatment

The effect of fluoroacetate, an inhibitor of the citric acid cycle, on the mixed-function oxidation of p-nitroanisole in isolated perfused livers from fed rats was studied. The citric acid cycle was inhibited by injection of 5 mg/kg sodium fluoroacetate into rats 3 hr prior to liver perfusion experiments. Inhibition of the citric acid cycle was marked by accumulation of citrate (5-fold) and decreases in rates of glycolysis and glycogenolysis by 50-90%. Fluoroacetate treatment inhibited mixed function oxidation in the perfused liver by about 50% without affecting p-nitroanisole O-demethylation by isolated microsomes. Fluorocitrate, at concentrations up to 50 microM, did not inhibit microsomal p-nitroanisole O-demethylation in vitro. These data support the hypothesis that mixed-function oxidation in intact hepatocytes is dependent upon reducing equivalents generated via the citric acid cycle.