title: An essential difference between the flavonoids monoHER and quercetin in their interplay with the endogenous antioxidant network.
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.
authors.affiliation: Department of Pharmacology and Toxicology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, Maastricht, The Netherlands. hilde.jacobs@maastrichtuniversity.nl
authors.forename: Hilde
authors.initials: H
authors.lastname: Jacobs
authors.forename: Mohamed
authors.initials: M
authors.lastname: Moalin
authors.forename: Aalt
authors.initials: A
authors.lastname: Bast
authors.forename: Wim J F
authors.initials: WJ
authors.lastname: van der Vijgh
authors.forename: Guido R M M
authors.initials: GR
authors.lastname: Haenen
mesh_terms: D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D001205:Ascorbic Acid / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D005419:Flavonoids / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006896:Hydroxyethylrutoside / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008956:Models, Chemical; D015394:Molecular Structure; D016877:Oxidants / Q000737:chemistry / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D011794:Quercetin / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology
chemical_list: C522803:7-monohydroxyethylrutoside; D000975:Antioxidants; D005419:Flavonoids; D006896:Hydroxyethylrutoside; D016877:Oxidants; D011794:Quercetin; D006861:Hydrogen Peroxide; D005978:Glutathione; D001205:Ascorbic Acid