Understanding the cellular effects of flavonoid metabolites is important for predicting which dietary flavonoids might be most beneficial in vivo. Here we investigate the bioactivity in dermal fibroblasts of the major reported in vivo metabolites of quercetin, i.e. 3′-O-methyl quercetin, 4′-O-methyl quercetin and quercetin 7-O-β-d-glucuronide, relative to that of quercetin, in terms of their further metabolism and their resulting cytotoxic and/or cytoprotective effects in the absence and presence of oxidative stress. Uptake experiments indicate that exposure to quercetin led to the generation of two novel cellular metabolites, one characterized as a 2′-glutathionyl quercetin conjugate and another product with similar spectral characteristics but 1 mass unit lower, putatively a quinone/quinone methide. A similar product was identified in cells exposed to 3′-O-methyl quercetin, but not in the lysates of those exposed to its 4′-O-methyl counterpart, suggesting that its formation is related to oxidative metabolism. There was no uptake or metabolism of quercetin 7-O-β-d-glucuronide by fibroblasts. Formation of oxidative metabolites may explain the observed concentration-dependent toxicity of quercetin and 3′-O-methyl quercetin, whereas the formation of a 2′-glutathionyl quercetin conjugate is interpreted as a detoxification step. Both O-methylated metabolites conferred less protection than quercetin against peroxide-induced damage, and quercetin glucuronide was ineffective. The ability to modulate cellular toxicity paralleled the ability of the compounds to decrease the level of peroxide-induced caspase-3 activation. Our data suggest that the actions of quercetin and its metabolites in vivo are mediated by intracellular metabolites.
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Research Article|
May 15 2003
Intracellular metabolism and bioactivity of quercetin and its in vivo metabolites
Jeremy P. E. SPENCER;
Jeremy P. E. SPENCER
Wolfson Centre for Age-Related Diseases, GKT School of Biomedical Sciences, Hodgkin Building, King's College, Guy's Campus, London SE1 9RT, U.K.
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Gunter G. C. KUHNLE;
Gunter G. C. KUHNLE
Wolfson Centre for Age-Related Diseases, GKT School of Biomedical Sciences, Hodgkin Building, King's College, Guy's Campus, London SE1 9RT, U.K.
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Robert J. WILLIAMS;
Robert J. WILLIAMS
Wolfson Centre for Age-Related Diseases, GKT School of Biomedical Sciences, Hodgkin Building, King's College, Guy's Campus, London SE1 9RT, U.K.
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Catherine RICE-EVANS
Catherine RICE-EVANS
1
Wolfson Centre for Age-Related Diseases, GKT School of Biomedical Sciences, Hodgkin Building, King's College, Guy's Campus, London SE1 9RT, U.K.
1To whom correspondence should be addressed (e-mail [email protected]).
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Publisher: Portland Press Ltd
Received:
December 20 2002
Revision Received:
January 28 2003
Accepted:
February 11 2003
Accepted Manuscript online:
February 11 2003
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2003
2003
Biochem J (2003) 372 (1): 173–181.
Article history
Received:
December 20 2002
Revision Received:
January 28 2003
Accepted:
February 11 2003
Accepted Manuscript online:
February 11 2003
Citation
Jeremy P. E. SPENCER, Gunter G. C. KUHNLE, Robert J. WILLIAMS, Catherine RICE-EVANS; Intracellular metabolism and bioactivity of quercetin and its in vivo metabolites. Biochem J 15 May 2003; 372 (1): 173–181. doi: https://doi.org/10.1042/bj20021972
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