title: Characterization of the glutathione conjugate of the semisynthetic flavonoid monoHER.
abstract: Flavonoids protect against oxidative stress by scavenging free radicals. During this protection flavonoids are oxidized. The oxidized flavonoids formed are often reactive. Consequently, protection by flavonoids can result in the formation of toxic products. In this study the oxidation of 7-mono-O-(beta-hydroxyethyl)rutoside (monoHER), which is a constituent of the registered drug Venoruton, was studied in the absence and presence of glutathione (GSH). MonoHER was oxidized by horseradish peroxidase/H(2)O(2). Spectrophotometric and HPLC analysis showed that in the presence of GSH, a monoHER-GSH conjugate was formed, which was identified as 2'-glutathionyl monohydroxyethylrutoside by mass spectrometric analysis and (1)H NMR. Preferential formation of this glutathione adduct in the B ring at C2' was confirmed by molecular quantum chemical calculations. This conjugate was also detected in the bile fluid of a healthy volunteer after iv administration of monoHER, demonstrating its formation in vivo. These results indicate that in the process of offering protection against free radicals, monoHER is converted into an oxidation product that is reactive toward thiols. The formation of this thiol-reactive oxidation product is potentially harmful. Thus, the supposed beneficial effect of monoHER as an antioxidant may be accompanied by the formation of products with an electrophilic, toxic potential.
authors.affiliation: Department of Pharmacology and Toxicology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre+, 6200 MD Maastricht, The Netherlands. hilde.jacobs@FARMACO.unimaas.nl
authors.forename: Hilde
authors.initials: H
authors.lastname: Jacobs
authors.forename: Wim J F
authors.initials: WJ
authors.lastname: van der Vijgh
authors.forename: Ger H
authors.initials: GH
authors.lastname: Koek
authors.forename: Guy J J
authors.initials: GJ
authors.lastname: Draaisma
authors.forename: Mohamed
authors.initials: M
authors.lastname: Moalin
authors.forename: Gino P F
authors.initials: GP
authors.lastname: van Strijdonck
authors.forename: Aalt
authors.initials: A
authors.lastname: Bast
authors.forename: Guido R M M
authors.initials: GR
authors.lastname: Haenen
mesh_terms: D000328:Adult; D001646:Bile / Q000737:chemistry; D001826:Body Fluids / Q000737:chemistry; D003198:Computer Simulation; D005978:Glutathione / Q000737:chemistry*; D006735:Horseradish Peroxidase / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry; D006896:Hydroxyethylrutoside / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000032:analysis / Q000737:chemistry; D007262:Infusions, Intravenous; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008956:Models, Chemical; D010084:Oxidation-Reduction; D011789:Quantum Theory; D012016:Reference Values; D052616:Solid Phase Extraction; D013056:Spectrophotometry, Ultraviolet; D013997:Time Factors
chemical_list: C522803:7-monohydroxyethylrutoside; D006896:Hydroxyethylrutoside; D006861:Hydrogen Peroxide; D006735:Horseradish Peroxidase; D005978:Glutathione