Antioxidants and their efficacy ? (Sanpaku & Dreiter)

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.

Selected papers:

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:

Acai polyphenols inhibiting cancer growth

Acai reducing pain and inflammation by inhibiting COX-1/COX-2

Acai and grape polyphenols reducing inflammation

Acai boosting the immune system

Polyphenolic-rich fruit and berry juice reduces pain

Acai consumption reducing metabolic disease risk factors

Acai reducing damage from smoking

Hibiscus anythocyanins inhibiting cancer growth

Hibiscus reducing cell mutation

Hibiscus reducing oxidative stress

Hibiscus polyphenols reducing oxidative stress

EGCG from green tea in stress reduction

Stinging nettle for prostate health

Rooibos for stress mediation

Strawberry phenols to reduce oxidative stress and artery plaque buildup

Wine as bloodstream fat reducer for prevention of heart disease

Polyphenols reducing damage caused by high-fat/high-carb meals

Flavonoids in orange juice mitigating inflammatory effect of sugar

Recommendation to consume high-antioxidant foods to prevent oxidative stress

High-antioxidant spice blend reduces insulin and TG response

Green veggies reducing affect of smoking on cervical cancer

Vitamins C and E from fruits/veggies to reduce nitrates and inhibit cancer

Inverse-correlation between carotenoid levels and fatigue, illness, smoking, and drinking

Antioxidant-rich foods for aging and health

Antioxidants improving endothelial function

Vegetable extracts reducing cancer proliferation

Fruit extracts to reduce protein oxidation in burgers

Antioxidant consumption to reduce COPD and improve lung function

Inverse correlation between fruit/veggie intake and COPD

Inverse correlation between soy consumption and COPD

High antioxidant intake and increased pulmonary function

Fruits and vitamin E for reducing COPD

Tea and fruit/veggie consumption to reduce COPD

Antioxidants for protection from lung disease

Increased antioxidant consumption and decreased breast cancer risk

Antioxidants and the prevention of Alzheimers

Phytoestrogens and increased lifespan

Green veggies to reduce skin cancer risk

Antioxidants to reduce endometrial cancer risk

Isoflavones to reduce cancer risk

High fruit consumption and colon health

Broccoli antioxidants and DNA repair

Broccoli antioxidants as anti-carcinogens

Broccoli sulphorophane to reduce cancer risk

Broccoli sulphorophane to kill cancer cells

Watercress to reduce cancer growth

Broccoli sprout extracts to reduce skin damage

Cruciferous extract for osteoarthritis

Isthiocyanates to inhibit tumor growth

Broccoli to improve bladder cancer survival

Citrus/veggie consumption to improve lymphoma survival

Chemopreventative effects of phytonutrients

Isothiocyanates to kill lung cancer cells

Sulforophane inhibits cancer cells

Broccoli sprouts to reduce breast cancer

Lignans and breast cancer risk reduction

Lignans to increase breast cancer survival

Fruits/veggies to decrease glaucoma risk

Antioxidants to reduce ovarian cancer risk

Fruits/veggies to prevent heart disease

Fruits/veggies to reduce coronary risks

Fresh fruit to reduce heart disease

Phenolic compounds to protect against Alzheimer’s

Organosulfer’s in garlic for antibacterial properties

Nitrites enhancing muscle activation

Citrus limonoids to improve health

Fruit/veggies and protection from smoking damage

Phytochemicals in cancer prevention and treatment

Phytonutrients and reduced inflammation

Phytonutrients to reduce endometrial cancer

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.



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