This is sort of a random post, but I remember coming across this paper from 2007 awhile back titled “The quercetin paradox” that shows how quercetin protects against some oxidative damage in a lung cell line but the oxidation product reacts with glutathione (GSH), lowering its concentration, which leads to an increase in LDH leakage and cytosolic free calcium (an apparent indication of cytotoxicity). So it was a neat example of a redirection of oxidative stress onto another antioxidant in the complex endogenous network. The authors wrote in the abstract:
Apparently, the potential toxicity of metabolites formed during the actual antioxidant activity of free radical scavengers should be considered in antioxidant supplementation.
2 of the authors of that paper (Haenen and Bast) recently published a new one in PLoS ONE that gives some insight into how small structural differences can have big differences on the network.
This time they tested a semi-synthetic flavonoid with a similar chemical structure to quercetin: semi-synthetic flavonoid 7-mono-O-(β-hydroxyethyl)-rutoside (monoHER). This is a constituent of the drug Venoruton, used to treat venous insufficiency. It is apparently being studied in conjunction with doxorubicin to protect against free radical induced cardiotoxicity. They also compared these results with quercetin itself.
As stated before, the body has a complex endogenous antioxidant system in which it passes along reactivity of oxidation products from antioxidant to antioxidant, and eventually the reactivity is diminished. Certain antioxidants can regenerate others and maintain the network (ascorbate and alpha-tocopherol is their example). Since a recent study found that monoHER is reactive toward thiols (the group on GSH that is responsible for its antioxidant property), the researchers checked if oxidized monoHER would react with GSH (and ascorbate).
Indeed, they found that the primary oxidation product of monoHER (monoHER quinone) reacts with GSH, and oxidized monoHER is reduced back to monoHER by ascorbate. This is similar to quercetin. BUT, oxidized quercetin reacts preferentially with thiols (GSH), while oxidized monoHER reacts preferentially with ascorbate.
It seems a good thing that even relatively high doses of quercetin don’t alter plasma antioxidant/oxidant balance in most in vivo human studies (e.g.), considering GSH is limited in plasma. Ascorbate is present in plasma, so it reduces oxidized monoHER so that it wouldn’t react with/damage protein thiols in the plasma, and and authors state that the oxidized ascorbate can be reduced for example by dehydroascorbate reductase / NADH. So monoHER it is better suited as a drug against oxidative stress in this way, by pushing the reactivity into the network, whereas quercetin does not.
Jacobs H, Moalin M, Bast A, van der Vijgh WJ, & Haenen GR (2010). An essential difference between the flavonoids monoHER and quercetin in their interplay with the endogenous antioxidant network. PloS one, 5 (11) PMID: 21079733