Inhibition of p-nitroanisole O-demethylation in perfused rat liver by oleate

Abstract

p-Nitroanisole O-demethylation in perfused livers from fasted, phenobarbital-treated rats was rapidly and reversibly inhibited by sodium oleate (0.3 to 0.6mM). Xylitol partially reversed this inhibitory effect. The inhibition was not mediated by a direct effect of oleate on musomal components since concentrations of oleate ranging up to 1.0 mM did not affect p-nitroanisole O-demethylation by isolated musomes. Infusion of 0.6 mM oleate did not alter the measured intracellular NAD +/NADH ratio but did cause a significant increase in the intracellular NADP +/NADPH ratio. A significant decrease in the ATP/ADP ratio was also observed. Oleoyl Co A inhibited p-nitroanisole O-demethylation in musomes ( K i about 30 μM), and both oleoyl Co A and palmitoyl CoA inhibited the energy-linked nicotinamide nucleotide transhydrogenase in submitochondrial particles ( K i about 1 μM). Thus, inhibition of mixed-function oxidation in the intact liver by oleate is most likely mediated by oleoyl CoA. Oleoyl CoA inhibits mixed-function oxidation in the intact liver by acting directly on cytochrome P-450 and by decreasing generation of NADPH via inhibition of key enzymes of the citric acid cycle and the energy-linked transhydrogenase.