Inhibition of mitochondrial proton F0F1-ATPase/ATP synthase by polyphenolic phytochemicals

Br J Pharmacol. 2000 Jul;130(5):1115-23. doi: 10.1038/sj.bjp.0703397.


Mitochondrial proton F0F1-ATPase/ATP synthase synthesizes ATP during oxidative phosphorylation. In this study, we examined the effects of several groups of polyphenolic phytochemicals on the activity of the enzyme. Resveratrol, a stilbene phytoalexin that is present in grapes and red wine, concentration-dependently inhibited the enzymatic activity of both rat brain and liver F0F1-ATPase/ATP synthase (IC(50) of 12 - 28 microM). Screening of other polyphenolic phytochemicals using rat brain F0F1-ATPase activity resulted in the following ranking potency (IC(50) in parenthesis): piceatannol (8 microM)>resveratrol (19 microM)=(-)epigallocatechin gallate (17 microM)>(-)epicatechin gallate, curcumin (45 microM)>genistein=biochanin A=quercetin=kaempferol=morin (55 - 65 microM)>phloretin=apigenin=daidzein (approx. 100 microM). Genistin, quercitrin, phloridzin, (+)catechin, (+)epicatechin, (-)epicatechin and (-)epigallocatechin had little effect at similar concentrations. Tannic acid, theaflavins (tea extract) and grape seed proanthocyanidin extract (GSPE) had IC(50) values of 5, 20 and 30 microg ml(-1), respectively. Several monophenolic antioxidants and non-phenolic compounds were ineffective at concentrations of 210 microM or higher. The inhibition of F0F1-ATPase by resveratrol and genistein was non-competitive in nature. The effects of polyphenolic phytochemicals were additive. Both resveratrol and genistein had little effect on the Na(+)/K(+)-ATPase activity of porcine cerebral cortex, whereas quercetin had similar inhibitory potency as for F0F1-ATPase. In conclusion, the ATP synthase is a target for dietary phytochemicals. This pharmacological property of these phytochemicals should be included in the examination of their health benefits as well as potential cytotoxicity.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Flavonoids / pharmacology
  • Genistein / pharmacology
  • Mitochondria / enzymology*
  • Phenols / pharmacology*
  • Polymers / pharmacology*
  • Proton-Translocating ATPases / antagonists & inhibitors*
  • Quercetin / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Resveratrol
  • Sodium-Potassium-Exchanging ATPase / antagonists & inhibitors
  • Stilbenes / pharmacology


  • Enzyme Inhibitors
  • Flavonoids
  • Phenols
  • Polymers
  • Stilbenes
  • Quercetin
  • Genistein
  • Proton-Translocating ATPases
  • Sodium-Potassium-Exchanging ATPase
  • Resveratrol