The minor structural difference between the antioxidants quercetin and 4'O-methylquercetin has a major impact on their selective thiol toxicity.
Antioxidants act as intermediates by picking up the high unselective reactivity of radicals and transferring it to other molecules. In this process the reactivity is reduced and becomes selective. This channeling of the reactivity can cause selective toxicity. The antioxidant quercetin is known to channel the reactivity towards thiol groups. The present study compares the thiol reactivity of quercetin with that of 4'O-methylquercetin (tamarixetin) towards creatine kinase (CK), a vital protein that contains a critical thiol moiety. Our results showed that oxidized quercetin and oxidized tamarixetin both adduct CK, which then loses its enzymatic function. Ascorbate, an important representative of the antioxidant network, is able to prevent adduction to and thus the inhibition of the enzyme by tamarixetin but not by quercetin. Apparently, tamarixetin is less thiol toxic than quercetin, because--rather than adduction to CK--tamarixetin quinone prefers to pass reactivity to the antioxidant network, i.e., to ascorbate. The findings exemplify that radical scavenging flavonoids pick up the reactivity of radicals and act as a pivot in directing the way the reactivity is channeled. A mere minor structural difference of only one methyl moiety between quercetin and tamarixetin appears to have a high impact on the selective, thiol toxicity.
Department of Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, P.O. Box 616, Maastricht 6200 MD, The Netherlands. kristien.lemmens@maastrichtuniversity.nl.
Kristien J A
KJ
Lemmens
Department of Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, P.O. Box 616, Maastricht 6200 MD, The Netherlands. m.vrolijk@maastrichtuniversity.nl.
Misha F
MF
Vrolijk
Department of Human Biology, Faculty of Health, Medicine and Life Sciences, Maastricht University, P.O. Box 616, Maastricht 6200 MD, The Netherlands. freek.bouwman@maastrichtuniversity.nl.
Freek G
FG
Bouwman
Department of Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, P.O. Box 616, Maastricht 6200 MD, The Netherlands. wjf.vandervijgh@maastrichtuniversity.nl.
Wim J F
WJ
van der Vijgh
Department of Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, P.O. Box 616, Maastricht 6200 MD, The Netherlands. a.bast@maastrichtuniversity.nl.
Aalt
A
Bast
Department of Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, P.O. Box 616, Maastricht 6200 MD, The Netherlands. g.haenen@maastrichtuniversity.nl.
Guido R M M
GR
Haenen
D000975:Antioxidants / Q000737:chemistry / Q000633:toxicity*; D003402:Creatine Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004187:Disaccharides / Q000737:chemistry / Q000633:toxicity*; D008958:Models, Molecular; D010084:Oxidation-Reduction; D011794:Quercetin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity*; D013438:Sulfhydryl Compounds / Q000378:metabolism*
D000975:Antioxidants; D004187:Disaccharides; D013438:Sulfhydryl Compounds; C508967:tamarixetin; D011794:Quercetin; D003402:Creatine Kinase