Mechanisms of toxic action of the flavonoid quercetin and its phase II metabolites

During and after absorption in the intestine, quercetin is extensively metabolised by the phase II biotransformation system. Because the biological activity of flavonoids is dependent on the number and position of free hydroxyl groups, a first objective of this thesis was to investigate the consequences of phase II metabolism of quercetin for its biological activity. For this purpose, a set of analysis methods comprising HPLC-DAD, LC-MS and 1 H NMR proved to be a useful tool in the identification of the phase II metabolite pattern of quercetin in various biological systems. These studies showed that the 3'- and 4'-hydroxyl groups of quercetin, (catechol hydroxyl groups) were important targets for methylation, sulfation and glucuronidation. Methylation of a catechol hydroxyl group of quercetin proved to decrease the pH-dependent radical scavenging capacity of the compound, both by increasing its pK a for deprotonation and by decreasing its electron-donating properties. Methylation of a catechol hydroxyl group had a similar effect as replacement of the hydroxyl group by a hydrogen atom. Regarding the pro-oxidant properties of quercetin, methylation of a catechol hydroxyl group of quercetin did not eliminate the pro-oxidant chemistry of quercetin, reflected in the formation of covalent adducts with glutathione upon oxidation of quercetin by horseradish peroxidase. However, methylated quercetin proved to form only 42% of the level of DNA adducts in exposed cells as compared to a similar amount of unconjugated quercetin, indicating that methylation of quercetin attenuates also this biological reactivity towards DNA.A second objective of this thesis was to obtain more insight into the possible toxic effects of quercetin by studying various mechanisms that might be relevant in the context of carcinogenesis. Quercetin appeared to have a biphasic effect on the proliferation of cancer cell lines expressing the estrogen receptor (ER). The stimulation of cancer cell proliferation was ER-dependent and appeared to occur at concentrations that are physiologically relevant in humans. With respect to the pro-oxidant activity of quercetin, peroxidase- and tyrosinase-type oxidative enzyme activity did not play a major role in the intracellular formation of covalent adducts of quercetin with DNA and protein, indicating that the formation of covalent adducts of quercetin with cellular macromolecules might also be relevant in cell types lacking oxidative enzyme activity. Furthermore, the covalent quercetin DNA adducts were of transient nature, which may either eliminate or attenuate the adverse effects of covalent DNA adduct formation. The studies presented in this thesis provided indications for the dualistic character of quercetin, regarding its role in the process of cancer development.

Bibliographic Details

Main Author:	van der Woude, H.
Other Authors:	Rietjens, Ivonne
Format:	Doctoral thesis biblioteca
Language:	English
Published:	Ponsen & Looijen
Subjects:	metabolic detoxification, mode of action, quercetin, risk assessment, metabolische detoxificatie, quercetine, risicoschatting, werkwijze,
Online Access:	https://research.wur.nl/en/publications/mechanisms-of-toxic-action-of-the-flavonoid-quercetin-and-its-pha
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