Prooxidant activity of fisetin: effects on energy metabolism in the rat liver.
Flavonols, which possess the B-catechol ring, as quercetin, are capable of producing o-hemiquinones and to oxidize NADH in a variety of mammalian cells. The purpose of this study was to investigate whether fisetin affects the liver energy metabolism and the mitochondrial NADH to NAD+ ratio. The action of fisetin on hepatic energy metabolism was investigated in the perfused rat liver and isolated mitochondria. In isolated mitochondria, fisetin decreased the respiratory control and ADP/O ratios with the substrates α-ketoglutarate and succinate. In the presence of ADP, respiration of isolated mitochondria was inhibited with both substrates, indicating an inhibitory action on the ATP-synthase. The stimulation of the ATPase activity of coupled mitochondria and the inhibition of NADH-oxidase activity pointed toward a possible uncoupling action and the interference of fisetin with mitochondrial energy transduction mechanisms. In livers from fasted rats, fisetin inhibited ketogenesis from endogenous sources. The β-hydroxybutyrate/ acetoacetate ratio, which reflects the mitochondrial NADH/NAD+ redox ratio, was also decreased. In addition, fisetin (200 μM) increased the production of (14)CO2 from exogenous oleate. The results of this investigation suggest that fisetin causes a shift in the mitochondrial redox potential toward a more oxidized state with a clear predominance of its prooxidant activity.
Laboratory of Liver Metabolism, Department of Biochemistry, University of Maringá, 87020900 Maringá, Brazil.
Rodrigo Polimeni
RP
Constantin
Jorgete
J
Constantin
Clairce Luzia Salgueiro
CL
Pagadigorria
Emy Luiza
EL
Ishii-Iwamoto
Adelar
A
Bracht
Cristiane Vizioli
CV
de Castro
Nair Seiko
NS
Yamamoto
D020155:3-Hydroxybutyric Acid / Q000378:metabolism; D000090:Acetoacetates / Q000378:metabolism; D000818:Animals; D004734:Energy Metabolism; D005419:Flavonoids / Q000494:pharmacology*; D044948:Flavonols; D007656:Ketoglutaric Acids / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D011794:Quercetin / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D000090:Acetoacetates; D005419:Flavonoids; D044948:Flavonols; D007656:Ketoglutaric Acids; D009243:NAD; C016635:acetoacetic acid; D011794:Quercetin; C017875:fisetin; D020155:3-Hydroxybutyric Acid