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Pro-oxidant behaviour of antioxidants, and hormesis

hormesis antioxidants pro-oxidants

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#1 proileri

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Posted 26 March 2015 - 06:54 PM


These are some general things I've been thinking lately, and I thought to share them for wider scrutiny, even at this early stage. 

 

It seems that when it comes to anti/pro-oxidant behaviour, most antioxidants follow a U-shaped curve: In lower concentrations the anti-oxidants scavenge ROS and reduce oxidative stress - but in higher concentrations, the breakdown of antioxidants leads into greater oxidative stress. This seems to be true for most antioxidants: Vitamin C, reservatrol, plant polyphenols etc. On the other hand, the reason why plant polyphenols etc. can be beneficial, is exactly the oxidative stress - the temporary oxidative stress leads into upregulation of cellular redox system, which lowers the long-term oxidative stress.   

 

So, I'm wondering, what does this mean when it comes to antioxidant dosage? It seems to become an optimization game: minimize oxidative stress in general, while maximizing hormetic response with optimal stress-to-hormesis 'pulses'. So, if you want both the antioxidant and hormetic benefits, it seems that you should ingest a small daily dosage of antioxidants, that optimally reduce the general level of oxidative stress, and you should occasionally take a larger amount, which stresses your system and leads to hormesis. When looking at research, I'm having difficulty of locating any studies where antioxidants have been studied in such cyclic manner, though. Most studies have noted that antioxidants don't affect the lifespan - but then again, I suppose most studies use high doses of antioxidants ingested every day, which would mean that there might be so much daily stress that counter-acts any benefits. 

 

If 'antioxidant cycling' is a thing, it could also be one reason why 'varied diet rich with veggies and fruit' seems to be healthy: if you eat different foods rich with different vitamins, polyphenols etc. on different days, so you get temporary hormetic stress of different kind, but not every day.

 

In my mind, I'm comparing antioxidants to other behaviour that we know causes hormetic responses: exercise. Cardio-style exercise has wide range of benefits, reducing risk of most diseases and reducing mortality up to 50%(!) - and most of these come from hormetic responses to a repeated short period of stress. From exercise studies, we know that there is also a U-shaped curve when it comes to reducing risk of mortality. Optimal response seems to be induced by something like 30-90 minutes of moderate exercise repeated a few times per week, so roughly speaking "1h of moderate stress every other day". With huge exercise amounts, the benefits diminish towards non-exerciser's levels. Similar thing might be true for antioxidant intake; maybe antioxidants are better every other day or so. 

 

Then again, I have no idea how exercise-induced hormesis and different amounts of antioxidants mix, or how does the hormetic response differ when it comes to exercise or diet-based source.

 

Thoughts?



#2 Darryl

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Posted 26 March 2015 - 07:41 PM

Only a few direct antioxidants are well absorbed: Vitamins C & E, carotenoids, and ergothioneine. No plant polyphenol at dietary intakes achieves plasma peaks above the μM range, which is several orders of magnitude lower than uric acid and vitamin C (extracellular) and glutathione (intracellular). Most dietary antioxidants are hence irrelevant as in vivo direct antioxidants.

 

If none of the benefits of non-vitamin phytochemicals is due to direct antioxidant effects, perhaps their prooxidant effects are more important. We know how this usually works with the phenols. They give up a hydrogen or two to initial antioxidant activity, autooxidation, or oxidation by a cytochrome P450, becoming prooxidant quinones or semiquinones. These react with the free cysteine residues of Keap1, a protein that keeps (!) the transcription factor Nrf2 in the cytoplasm, When its cysteines are bound by electrophiles, Keap1 changes conformation, releasing Nrf2 to enter the nucleus and initiate 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).

 

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This is related to why phytochemical indirect antioxidants exhibit hepatoxicity at very high doses. Those green tea polyphenols aren't just antioxidants, they're cycling between phenol and quinone, consuming glutathione for reduction, and at overdose levels will deplete liver reduced glutathione in much the same manner as acetaminophen.

 

Once we make the distinction between well absorbed direct antioxidants, and poorly absorbed xenobiotic redox cyclers that happen to initially function as quenchers in the test tube, we can identify two different hormetic response curves. The few effective direct antioxidants: are obviously beneficial at very low doses, active in signalling and preventing unchecked radical damage. In excess they interferee with normal cell signalling by low-level RNOS (NO, O2, H2O2, H2S, etc), impairing adaptation to stress. The many xenobiotic hormetins: at low doses activate endogenous antioxidant responses; in excess many are redox cyclers that can both attack macromolecules and deplete endogenous antioxidants.

 

In neither case do normal dietary doses enter the hazardous range, its supplement isolates and extracts that create issues. I don't take supplements of any of the direct antioxidants, as I aim to get them from diet. I supplement a few better studied xenobiotic hormetins (andrographolide, curcumin) at a fraction of published trial doses, as my diet isn't always broccoli sprouts and green tea.


Edited by Darryl, 26 March 2015 - 07:52 PM.

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#3 timar

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Posted 26 March 2015 - 08:56 PM

Darryl, do you have some studies at hand regarding the absorption kinetics of ergothioneine? We know that the active transport mechanisms for vitamins C and E become saturated with high doses, how about ergothioneine? I think this is an interesting question since there's probably a much wider variation in intake than for the other antioxidant vitamins. For example, I enjoy gathering mushrooms in the local forests and last autumn I gathered and dried humungous amounts of various edible boletus species which I now eat on a regular basis (Risotto ai funghi, wonderful!). As mushrooms have ergothioneine levels an order of magnitude above other food sources, and boletus rank highest among mushrooms, I wonder if I may actually end up megadosing a potent antioxidant...


Edited by timar, 26 March 2015 - 09:01 PM.


#4 Darryl

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Posted 27 March 2015 - 05:14 PM

Timar, there appears little in the literature examining ergothioneine absorption kinetics at high doses - most research seems to be in depletion studies through the 50s and 60s, seeking a deficiency syndrome (and hence, vitamin discovery). This review covers what was known until very recently:

 

Cheah, I. K., & Halliwell, B. (2012). Ergothioneine; antioxidant potential, physiological function and role in diseaseBiochimica et Biophysica Acta (BBA)-Molecular Basis of Disease1822(5), 784-793.

 

There's likely an autoregulatory loop between inflammatory cytokines and expression of the ergothioneine transporter, contributing to keeping tissue levels constant.

 

Taubert, D., Jung, N., Goeser, T., & Schömig, E. (2009). Increased ergothioneine tissue concentrations in carriers of the Crohn’s disease risk-associated 503F variant of the organic cation transporter OCTN1Gut58(2), 312-314.

Maeda, T., Hirayama, M., Kobayashi, D., Miyazawa, K., & Tamai, I. (2007). Mechanism of the regulation of organic cation/carnitine transporter 1 (SLC22A4) by rheumatoid arthritis-associated transcriptional factor RUNX1 and inflammatory cytokinesDrug metabolism and disposition35(3), 394-401.

 

 


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#5 timar

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Posted 27 March 2015 - 06:31 PM

Thank you, Darryl. If you haven't found such studies I guess I don't need to look any further. ;)

 

The Halliwell review is really fascinating. I hope it will stimulate more research into this neglected vitamin. Until then, I put my trust into the fact that those mushrooms have been traditionally consumed in large amounts, particularly in Eastern Europe, and prized for their health benefits.


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#6 Dorian Grey

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Posted 28 March 2015 - 04:51 PM

Looking forward to your book Darryl.  Until then, any opinion on phytic acid / IP6?  

 

It seems to me simply reducing free/unbound transition metals might have a "sparing effect" on most any/all dietary and/or supplemental antioxidants, thus reducing the need for supplementation and boosting effectiveness of normal and natural antioxidant mechanisms.  

 

Rather than mega-dosing multiple anti-ox supps or superfoods, simply lower the catalyst that normally burns through antioxidants...  The best of both worlds?  Any downside to this other than the possibility of anemia or over-chelating important trace min's (mag/zinc)?

 

Thanks so much for your contributions to this forum...  For all you do, We Salute You!  


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#7 nowayout

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Posted 29 March 2015 - 03:44 PM

Also, you should keep in mind that supplementary antioxidants can prevent hormesis from exercise - some of us try to get around this problem by timing of intake but whether this works is an open question.  In comparison to exercise, any beneficial effect of supplementary antioxidants appears to be small anyway.  







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