An Essential Difference between the Flavonoids MonoHER and Quercetin in Their Interplay with the Endogenous Antioxidant Network

Department of Pharmacology and Toxicology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, Maastricht, The Netherlands.
PLoS ONE (Impact Factor: 3.23). 11/2010; 5(11):e13880. DOI: 10.1371/journal.pone.0013880
Source: PubMed

ABSTRACT Antioxidants can scavenge highly reactive radicals. As a result the antioxidants are converted into oxidation products that might cause damage to vital cellular components. To prevent this damage, the human body possesses an intricate network of antioxidants that pass over the reactivity from one antioxidant to another in a controlled way. The aim of the present study was to investigate how the semi-synthetic flavonoid 7-mono-O-(β-hydroxyethyl)-rutoside (monoHER), a potential protective agent against doxorubicin-induced cardiotoxicity, fits into this antioxidant network. This position was compared with that of the well-known flavonoid quercetin. The present study shows that the oxidation products of both monoHER and quercetin are reactive towards thiol groups of both GSH and proteins. However, in human blood plasma, oxidized quercetin easily reacts with protein thiols, whereas oxidized monoHER does not react with plasma protein thiols. Our results indicate that this can be explained by the presence of ascorbate in plasma; ascorbate is able to reduce oxidized monoHER to the parent compound monoHER before oxidized monoHER can react with thiols. This is a major difference with oxidized quercetin that preferentially reacts with thiols rather than ascorbate. The difference in selectivity between monoHER and quercetin originates from an intrinsic difference in the chemical nature of their oxidation products, which was corroborated by molecular quantum chemical calculations. These findings point towards an essential difference between structurally closely related flavonoids in their interplay with the endogenous antioxidant network. The advantage of monoHER is that it can safely channel the reactivity of radicals into the antioxidant network where the reactivity is completely neutralized.

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Available from: Guido Haenen, Aug 05, 2014
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    • "Moreover, antioxidant flavonoids do not act in isolation but cooperate with other antioxidants in an intricate network. For example, flavonoids can be recycled after scavenging by vitamin C or react with glutathione [17] [18] and some flavonoids can take over the antioxidant activity of vitamin E [19]. Especially the interaction with the endogenous antioxidant system will increase the ability of the body to adapt when homeostasis is challenged. "
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    ABSTRACT: Various health benefits of the cocoa flavanol (-)-epicatechin (EC) have been attributed to its antioxidant and anti-inflammatory potency. In the present study we investigated whether EC is able to prevent deterioration of the anti-inflammatory effect of the glucocorticoid (GC) cortisol in the presence of oxidative stress. It was found that cortisol reduces inflammation in differentiated monocytes. Oxidative stress extinguishes the anti-inflammatory effect of cortisol, leading to cortisol resistance. EC reduces intracellular oxidative stress as well as the development of cortisol resistance. This further deciphers the enigmatic mechanism of EC by which it exerts its anti-inflammatory and antioxidant action. The observed effect of the cocoa flavanol EC will especially be of relevance in pathophysiological conditions with increased oxidative stress and consequential GC resistance and provides a fundament for the rational use of dietary antioxidants.
    Pharmacological Research 11/2013; DOI:10.1016/j.phrs.2013.11.004 · 4.41 Impact Factor
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    • "In blood plasma, the monoHER quinone might, similar to the quercetin quinone, also react with protein thiols and cause toxicity. However, the monoHER quinone, in contrast to the quercetin quinone, reacts with ascorbate rather than with protein thiols [29]. "
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    ABSTRACT: During the scavenging of free radicals flavonoids are oxidized to electrophilic quinones. Glutathione (GSH) can trap these quinones, thereby forming GSH-flavonoid adducts. The aim of this study was to compare the stability of the GSH-flavonoid adduct of 7-mono-O-(β-hydroxyethyl)rutoside (monoHER) with that of quercetin. It was found that GSH-quercetin reacts with the thiol N-acetyl-L-cysteine (NAC) to form NAC-quercetin, whereas GSH-monoHER does not react with NAC. In addition, the adduct of the monoHER quinone with the dithiol dithiothreitol (DTT) is relatively stable, whereas the DTT-quercetin adduct is readily converted into quercetin and DTT disulfide. These differences in reactivity of the thiol-flavonoid adducts demonstrate that GSH-monoHER is much more stable than GSH-quercetin. This difference in reactivity was corroborated by molecular quantum chemical calculations. Thus, although both flavonoid quinones are rapidly scavenged by GSH, the advantage of monoHER is that it forms a stable conjugate with GSH, thereby preventing a possible spread of toxicity. These findings demonstrate that even structurally comparable flavonoids behave differently, which will be reflected in the biological effects of these flavonoids.
    Free Radical Biology and Medicine 12/2011; 51(11):2118-23. DOI:10.1016/j.freeradbiomed.2011.09.013 · 5.74 Impact Factor
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    • "GSH-monoHER formation is preceded by the oxidation of the catechol of monoHER, e.g., when it acts as an antioxidant by scavenging free radicals. Relatively low amounts of the GSH-monoHER conjugate were found, probably because there was no oxidative stress in these mice and because, as recently shown, the monoHER quinone reacts with the antioxidant ascorbate rather than with GSH (Jacobs et al., 2010). "
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    ABSTRACT: The clinical use of the anticancer drug doxorubicin is limited by severe cardiotoxicity. In mice, the semisynthetic antioxidant flavonoid 7-mono-O-(β-hydroxyethyl)-rutoside (monoHER) has been successfully used as a protector against doxorubicin-induced cardiotoxicity. However, most monoHER has already been cleared from the body at the time that doxorubicin concentrations are still high. This result suggests that not only the parent compound monoHER itself but also monoHER metabolites could be responsible for the observed cardioprotective effects in mice. Therefore, in the present study, we investigated the metabolism of monoHER in mice. Mice were administered 500 mg/kg monoHER intraperitoneally. At different time points after monoHER administration, bile was collected and analyzed for the presence of monoHER metabolites. The formed metabolites were identified by liquid chromatography-diode array detection-time of flight-mass spectrometry. Thirteen different metabolites were identified. The observed routes of monoHER metabolism are methylation, glucuronidation, oxidation of its hydroxyethyl group, GSH conjugation, and hydrolysis of its disaccharide. In line with other flavonoids, methylated monoHER and the monoHER glucosides are expected to have relatively high cellular uptake and low clearance from the body. Therefore, these metabolites might contribute to the observed protection of monoHER against doxorubicin-induced cardiotoxicity.
    Drug metabolism and disposition: the biological fate of chemicals 05/2011; 39(5):750-6. DOI:10.1124/dmd.110.036525 · 3.25 Impact Factor
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