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Chem Biol Interact. 2015 Sep 5;239:146-52. doi: 10.1016/j.cbi.2015.07.004. Epub 2015 Jul 8.

The contribution of the major metabolite 4'-O-methylmonoHER to the antioxidant activity of the flavonoid monoHER.

Author information

1
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.
2
Department of Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
3
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.

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.

KEYWORDS:

4′-O-methylmonoHER; Antioxidant activity; Doxorubicin; MethylmonoHER; MonoHER

PMID:
26163455
DOI:
10.1016/j.cbi.2015.07.004
[Indexed for MEDLINE]

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