Inhibition of p-nitroanisole O-demethylation in perfused rat liver by potassium cyanide.
The effect of potassium cyanide on p-nitroanisole O-demethylation in perfused rat livers has been examined. Cyanide (2 mM), an inhibitor of cytochrome oxidase, diminished p-nitroanisole O-demethylation by 50-75% in perfused livers from normal and phenobarbital-treated rats, but had much less effect on hepatic microsomal p-nitroanisole O-demethylation. The inhibition was also observed in livers where the activity of the pentose phosphate shunt was abolished by pretreatment with 6-aminonicotinamide. Cyanide infusion decreased hepatic ATP/ADP ratios and cellular concentrations of glutamate, alpha-ketoglutarate, and isocitrate, but caused an increase in the NADP+/NADPH ratio. Rates of NADPH generation via the pentose phosphate shunt were unchanged by cyanide, and hepatic concentrations of glucose 6-phosphate were markedly increased by cyanide. Thus, inhibition of p-nitroanisole metabolism could not be explained solely by a direct interaction of cyanide with mixed-function oxidases or diminished NADPH generation via the pentose cycle. These data indicate that cyanide inhibits mixed-function oxidation in intact cells by diminishing the generation of NADPH from sources other than the pentose cycle. Further, these data are consistent with the hypothesis that some NADPH for mixed-function oxidation arises from cyanide-sensitive mitochondrial sources.
D000818:Animals; D003486:Cyanides / Q000494:pharmacology*; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors; D005260:Female; D008099:Liver / Q000201:enzymology*; D008862:Microsomes, Liver / Q000201:enzymology; D009575:Nitroanisole O-Demethylase / Q000037:antagonists & inhibitors*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D010428:Pentosephosphates / Q000378:metabolism; D010477:Perfusion; D010634:Phenobarbital / Q000494:pharmacology; D011190:Potassium Cyanide / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D003486:Cyanides; D010428:Pentosephosphates; D009575:Nitroanisole O-Demethylase; D010088:Oxidoreductases; D003576:Electron Transport Complex IV; D011190:Potassium Cyanide; D010634:Phenobarbital