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

1 Mitochondrial proton FOF1-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. 2 Resveratrol, a stilbene phytoalexin that is present in grapes and red wine, concentration-dependently inhibited the enzymatic activity of both rat brain and liver FOF1-ATPase/ATP synthase (IC50 of 12-28 mu M). 3 Screening of other polyphenolic phytochemicals using rat brain F0F1-ATPase activity resulted in the following ranking potency (IC50 in parenthesis): piceatannol (8 mu M) > resveratrol (19 mu M)= (-)epigallocatechin gallate (17 mu M)>(-)epicatechin gallate, curcumin (45 mu M) > genistein = biochanin A = quercetin = kaempferol = morin (55 - 65 mu M) > phloretin = apigenin = daidzein (approx. 100 mu 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 IC50 values of 5, 20 and 30 mu g ml(-1), respectively. Several monophenolic antioxidants and non-phenolic compounds were ineffective at concentrations of 210 mu M or higher. 4 The inhibition of F0F1-ATPase by resveratrol and genistein was non-competitive in nature. 5 The effects of polyphenolic phytochemicals were additive. 6 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. 7 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.