Regulation of p-nitroanisole O-demethylation in perfused rat liver. Adenine nucleotide inhibition of NADP+-dependent dehydrogenases and NADPH-cytochrome c reductase.
Perfusion of rat livers with 10 mM-fructose or pretreatment of the rat with 6-aminonicotinamide (70 mg/kg) 6 h before perfusion decreased intracellular ATP concentrations and increased the rate of p-nitroanisole O-demethylation. This increase was accompanied by a decrease in the free [NADP+]/[NADPH] ratio calculated from concentrations of substrates assumed to be in near-equilibrium with isocitrate dehydrogenase. After pretreatment with 6-aminonicotinamide the [NADP+]/[NADPH] ratio also declined. Reduction of NADP+ during mixed-function oxidation may be explained by inhibition of of one or more NADPH-generating enzymes. Glucose 6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, isocitrate dehydrogenase and "malic" enzyme, partially purified from livers of phenobarbital-treated rats, were inhibited by ATP and ADP. Inhibitor constants of ATP for the four dehydrogenases varied considerably, ranging from 9 micrometer for "malic" enzyme to 1.85 mM for glucose 6-phosphate dehydrogenase. NADPH-cytochrome c reductase was also inhibited by ATP (Ki 2.8 mM) and by ADP (Ki 0.9 mM), but not by AMP. Concentrations of ATP and ADP that inhibited glucose 6-phosphate dehydrogenase and the reductase were comparable with concentrations in the intact liver. Thus agents that lower intracellular ATP may accelerate rates of mixed-function oxidation by a concerted mechanism involving deinhibition of NADPH-cytochrome c reductase and one or more NADPH-generating enzymes.
D015120:6-Aminonicotinamide / Q000494:pharmacology; D000227:Adenine Nucleotides / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000840:Anisoles / Q000378:metabolism*; D005260:Female; D005632:Fructose / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors*; D009249:NADP / Q000378:metabolism; D009252:NADPH Dehydrogenase / Q000037:antagonists & inhibitors*; D009251:NADPH-Ferrihemoprotein Reductase / Q000037:antagonists & inhibitors*; D009575:Nitroanisole O-Demethylase / Q000378:metabolism; D009596:Nitrophenols / Q000378:metabolism; D010084:Oxidation-Reduction; D010477:Perfusion; D051381:Rats
D000227:Adenine Nucleotides; D000840:Anisoles; D009596:Nitrophenols; D005632:Fructose; D015120:6-Aminonicotinamide; D009249:NADP; D000255:Adenosine Triphosphate; D009575:Nitroanisole O-Demethylase; D009247:NADH, NADPH Oxidoreductases; D009251:NADPH-Ferrihemoprotein Reductase; D009252:NADPH Dehydrogenase; C005306:4-nitroanisole