title: The contribution of the major metabolite 4'-O-methylmonoHER to the antioxidant activity of the flavonoid monoHER.
abstract: The antioxidant flavonoid 7-mono-O-(β-hydroxyethyl)-rutoside (monoHER) effectively protects against doxorubicin-induced cardiotoxicity in mice. Doxorubicin is a very effective anticancer drug. The clinical use of doxorubicin is limited by severe cardiotoxicity. Free radicals, i.e., hydroxyl and superoxide radicals play a crucial role in this toxicity. In this study the involvement of the major metabolite of monoHER, 4'-O-methylmonoHER (methylmonoHER) in the protective effect of monoHER is studied. MethylmonoHER displayed antioxidant activity i.e., TEAC, hydroxyl and superoxide radical scavenging activity; nevertheless monoHER appeared to be superior compared to methylmonoHER. As a result of scavenging, flavonoids are oxidized and display reactivity towards thiols. Oxidized methylmonoHER, is far less thiol reactive towards creatine kinase than monoHER, which indicates that methylmonoHER is less toxic towards thiol containing enzymes. The thiol-reactivity of oxidized methylmonoHER was also negligible towards KEAP1 compared to monoHER. These results indicate that methylmonoHER hardly protects against radical damage via scavenging or via activating the NRF2 defense system. Also in HUVECs, methylmonoHER provided far less protection against oxidative stress (EC50>100μM) than monoHER which was a very potent protector (EC50=80nM). The results indicate that the contribution of methylmonoHER to the protection against doxorubicin-induced cardiotoxicity by monoHER is relatively low.
authors.affiliation: Department of Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands. Electronic address: kristien.lemmens@maastrichtuniversity.nl.
authors.forename: Kristien J A
authors.initials: KJ
authors.lastname: Lemmens
authors.affiliation: Department of Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
authors.forename: Pauline M
authors.initials: PM
authors.lastname: Herst
authors.affiliation: Department of Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
authors.forename: Bas A C
authors.initials: BA
authors.lastname: Housmans
authors.affiliation: Department of Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Moalin
authors.affiliation: Department of Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
authors.forename: Wim J F
authors.initials: WJ
authors.lastname: van der Vijgh
authors.affiliation: Department of Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
authors.forename: Aalt
authors.initials: A
authors.lastname: Bast
authors.affiliation: Department of Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands. Electronic address: g.haenen@maastrichtuniversity.nl.
authors.forename: Guido R M M
authors.initials: GR
authors.lastname: Haenen
mesh_terms: D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology*; D003402:Creatine Kinase / Q000378:metabolism; D004317:Doxorubicin / Q000009:adverse effects; D016166:Free Radical Scavengers / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D006896:Hydroxyethylrutoside / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D017665:Hydroxyl Radical / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D018384:Oxidative Stress / Q000187:drug effects*; D012431:Rutin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism
chemical_list: C000602899:4'-methyl-7-mono-O-(beta-hydroxyethyl)rutoside; C522803:7-monohydroxyethylrutoside; D000975:Antioxidants; D016166:Free Radical Scavengers; D006896:Hydroxyethylrutoside; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D013481:Superoxides; D017665:Hydroxyl Radical; D012431:Rutin; D004317:Doxorubicin; D003402:Creatine Kinase; D005978:Glutathione
keywords: 4′-O-methylmonoHER; Antioxidant activity; Doxorubicin; MethylmonoHER; MonoHER