title: The quercetin paradox.
abstract: Free radical scavenging antioxidants, such as quercetin, are chemically converted into oxidation products when they protect against free radicals. The main oxidation product of quercetin, however, displays a high reactivity towards thiols, which can lead to the loss of protein function. The quercetin paradox is that in the process of offering protection, quercetin is converted into a potential toxic product. In the present study, this paradox is evaluated using rat lung epithelial (RLE) cells. It was found that quercetin efficiently protects against H(2)O(2)-induced DNA damage in RLE cells, but this damage is swapped for a reduction in GSH level, an increase in LDH leakage as well as an increase of the cytosolic free calcium concentration. To our knowledge, this is the first study that indicates that the quercetin paradox, i.e. the exchange of damage caused by quercetin and its metabolites, also occurs in living lung cells. Following depletion of GSH in the cells by BSO pre-treatment, this quercetin paradox becomes more pronounced, confirming that the formation of thiol reactive quercetin metabolites is involved in the quercetin paradox. The quercetin paradox in living cells implies that the anti-oxidant directs oxidative damage selectively to thiol arylation. Apparently, the potential toxicity of metabolites formed during the actual antioxidant activity of free radical scavengers should be considered in antioxidant supplementation.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medicine, University of Maastricht, PO Box 616, 6200 MD Maastricht, The Netherlands. a.boots@farmaco.unimaas.nl
authors.forename: Agnes W
authors.initials: AW
authors.lastname: Boots
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Roel P F
authors.initials: RP
authors.lastname: Schins
authors.forename: Rodger
authors.initials: R
authors.lastname: Duffin
authors.forename: Johan W M
authors.initials: JW
authors.lastname: Heemskerk
authors.forename: Aalt
authors.initials: A
authors.lastname: Bast
authors.forename: Guido R M M
authors.initials: GR
authors.lastname: Haenen
mesh_terms: D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D004249:DNA Damage; D004591:Electrophoresis, Polyacrylamide Gel; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors / Q000633:toxicity; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008171:Lung Diseases / Q000139:chemically induced / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D011794:Quercetin / Q000494:pharmacology*; D051381:Rats
chemical_list: D000963:Antimetabolites; D016166:Free Radical Scavengers; D019328:Buthionine Sulfoximine; D011794:Quercetin; D006861:Hydrogen Peroxide; D007770:L-Lactate Dehydrogenase; D005978:Glutathione; D002118:Calcium