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

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 μ M ). Screening of other polyphenolic phytochemicals using rat brain F0F1‐ATPase activity resulted in the following ranking potency (IC 50 in parenthesis): piceatannol (8 μ M )>resveratrol (19 μ M )=(−)epigallocatechin gallate (17 μ M )>(−)epicatechin gallate, curcumin (45 μ M )>genistein=biochanin A=quercetin=kaempferol=morin (55–65 μ M )>phloretin=apigenin=daidzein (approx. 100 μ M ). 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 μg ml −1 , respectively. Several monophenolic antioxidants and non‐phenolic compounds were ineffective at concentrations of 210 μ M 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.British Journal of Pharmacology (2000) 130 , 1115–1123; doi: 10.1038/sj.bjp.0703397