My understanding is that polyphenol antioxidants that predominate in vitro antioxidant assays from healthy diets don’t function primarily as direct antioxidants in the body. They’re upregulating endogenous stress responses.
Achievable tissue concentrations of polyphenols are only 2-4% those of endogenous antioxidants like uric acid, glutathione, and bilirubin. The effect of fruit on plasma antioxidant status appears to result from fructose increasing uric acid, and secondarily from inhibition of NF-κB to modulate inflammatory responses like the superoxide producing NADPH oxidases. Polyphenols, through autooxidation, cytochromes, or their intitial antioxidant activity, form semiquinone radicals and quinones with prooxidant potential. For example cancer cells in culture can be killed by reactive oxygen species generated by high doses of green tea polyphenols. The semiquinone and quinone moieties of oxidized polyphenols react with Keap1, releasing Nrf2 to enter the nucleus. Nrf2 initiates the transcription of of cytoprotective genes, including those for glutathione synthesis / recycling and other endogenous antioxidant enzymes, as well as DNA repair, protein chaperones, metal chelators, and toxin export; over 200 « Phase II response » or « antioxidant response element » genes are known. Nrf2 activation also downregulates NF-κB mediated proinflammatory responses, and this may be the major pathway for NF-κB inhibition by polyphenols.
Endogenous antioxidants are present in higher concentrations, and antioxidant enzymes like superoxide dismutase have faster reaction rates, than dietary antioxidants, and are hence orders of magnitude more potent. Unlike most dietary antioxidants, they’re catalytic (meaning they’re restored to full potency after scavenging radicals), and their levels can remain elevated for days after Nrf2 induction. Moreover, as their enzymatic activity is feedback regulated on short timescales, they can rapidly respond to deletorious spikes in reactive oxygen species, while permitting basal low levels of ROS etc. used in intracellular signalling. Exogenous antioxidants lack this innate « intelligence », which may account for some harms with antioxidant supplementation.
Specific polyphenols have other effects modulating cell regulation, acting in drug-like ways (active site and allosteric activation / inhibition). In general in vitro antioxidant assays like ORAC say very little about how polyphenols actually function in the body.
The major exceptions among dietary antioxidants are vitamins C & E and the carotenoids, which do function effectively as direct antioxidants in vivo and have had mostly disappointing results as supplements in clinical trials. Tissue levels of C are under tight regulation, restricted to about 70 μM in plasma, perhaps to reduce prooxidative reactions with free iron. Carotenoids are weak chemical quenchers, but excel at physical quenching of UV generated singlet oxygen. I’ve yet to study how/whether the body restricts E intake.
Zhang, Q., Pi, J., Woods, C. G., & Andersen, M. E. (2010). A systems biology perspective on Nrf2-mediated antioxidant response. Toxicology and applied pharmacology, 244(1), 84-97.
Niki, E. (2012). Do antioxidants impair signaling by reactive oxygen species and lipid oxidation products?. FEBS letters, 586(21), 3767-3770.
Forman, H. J., Davies, K. J., & Ursini, F. (2014). How do nutritional antioxidants really work: Nucleophilic tone and para-hormesis versus free radical scavenging in vivo. Free Radical Biology and Medicine, 66, 24-35.
Now, for the positive antioxidant studies I can dig up quick:
So, anyway, take what you will from this list. Personally I believe everyone should strive to consume as many antioxidants as they can, since only protective benefits have been shown, and there doesn’t appear to be an upper limit we can realisitically run into. However, this doesn’t mean extracts, it means whole fruits, veggies, spices, and beans. These foods are also high in fiber, vitamins, minerals, and water, all of which have health benefits and are good for us anyway.