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‐hemi‐ quinones 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 14CO2 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. © 2010 Wiley Periodicals, Inc. J Biochem Mol Toxicol 25:117–126, 2011; View this article online at wileyonlinelibrary.com. DOI 10.1002/jbt.20367