Inhibition of p-nitroanisole O-demethylation in perfused rat liver by oleate.
p-Nitroanisole O-demethylation in perfused livers from fasted, phenobarbital-treated rats was rapidly and reversibly inhibited by sodium oleate (0.3 to 0.6 mM). Xylitol partially reversed this inhibitory effect. The inhibition was not mediated by a direct effect of oleate on microsomal components since concentrations of oleate ranging up to 1.0 mM did not affect p-nitroanisole O-demethylation by isolated microsomes. 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 CoA inhibited p-nitroanisole O-demethylation in microsomes (Ki about 30 microM), and both oleoyl CoA and palmitoyl CoA inhibited the energy-linked nicotinamide nucleotide transhydrogenase in submitochondrial particles (Ki about 1 microM). 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.
D000214:Acyl Coenzyme A / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D000840:Anisoles / Q000378:metabolism*; D003640:Dealkylation; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D005415:Flavins / Q000032:analysis; D005453:Fluorescence; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D009243:NAD / Q000032:analysis; D009250:NADP Transhydrogenases / Q000037:antagonists & inhibitors; D019301:Oleic Acid; D009829:Oleic Acids / Q000494:pharmacology*; D010084:Oxidation-Reduction; D051381:Rats
D000214:Acyl Coenzyme A; D000840:Anisoles; D005227:Fatty Acids; D005415:Flavins; D009829:Oleic Acids; D009243:NAD; D019301:Oleic Acid; D000255:Adenosine Triphosphate; D009250:NADP Transhydrogenases; C005306:4-nitroanisole