Inhibition of mixed-function oxidation of p-nitroanisole in perfused rat liver by 2,4-dinitrophenol |
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Authors: | Steven A Belinsky Lester A Reinke Frederick C Kauffman Ronald G Thurman |
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Institution: | 1. Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27514 USA;2. University of Maryland School of Medicine, Baltimore, Maryland 21201 USA |
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Abstract: | The effect of dinitrophenol (52 μm), an uncoupler of oxidative phosphorylation, on p-nitroanisole O-demethylation in the perfused rat liver was examined. Dinitrophenol inhibited p-nitroanisole metabolism 70% in perfused livers from fasted, phenobarbital-treated rats, and 30% in livers from normal rats, but had no effect on this reaction in isolated microsomes. Rates of p-nitroanisole O-demethylation in livers from fed, phenobarbitaltreated rats were not inhibited by dinitrophenol unless the pentose phosphate shunt was first inhibited by 6-aminonicotinamide pretreatment. Dinitrophenol diminished cellular concentrations of ATP and NADPH 30 and 50%, respectively. Since mixed-function oxidation requires NADPH, these data are consistent with the hypothesis that dinitrophenol interrupts the synthesis and/or transfer of reducing equivalents from the mitochondria into the extramitochondrial space by interfering with energy-dependent NADPH synthesis and substrate shuttle mechanisms.In addition, dinitrophenol diminished conjugation reactions 57 and 89% in all metabolic states studied, most likely because it decreased UDP-glucose levels considerably (40 to 60%). |
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Keywords: | Recipient of Research Scientist Career Development Award 2KO-AA-00033 to whom reprint requests should be addressed |
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