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

Abstract

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