The Minor Structural Difference between the Antioxidants Quercetin and 4'O-Methylquercetin Has a Major Impact on Their Selective Thiol Toxicity

Abstract

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.

Food-Derived Bioactives Can Protect the Anti-Inflammatory Activity of Cortisol with Antioxidant-Dependent and -Independent Mechanisms

“…The absence of the anti-inflammatory activity in our test system may be explained by the fact that, in an environment high in oxidants, Q may be converted into thiol-reactive quinone products as a result of the radical scavenging. These quinones can react with protein thiols, causing reduction or loss of their function [ 25 , 26 ].…”

Jaceidin Flavonoid Isolated from Chiliadenus montanus Attenuates Tumor Progression in Mice via VEGF Inhibition: In Vivo and In Silico Studies

“…Moreover, methylation of flavonoids increases their intestinal absorption, and oral bioavailability [ 36 , 37 ]. In addition, methoxylated flavonoids are less toxic to vital cellular compounds containing SH-groups compared to their hydroxylated analogues as in case of tamarixetin and quercetin [ 38 ].…”

Differential Impact of Flavonoids on Redox Modulation, Bioenergetics, and Cell Signaling in Normal and Tumor Cells: A Comprehensive Review

“…After consumption of quercetin in humans, glutathionyl quercetin adducts are found at low levels in urine, suggesting that the conjugation reaction can occur in vivo ( 101 ). The presence of ascorbate slows the oxidation of quercetin and inhibits formation of the quinone forms ( 131 ), but, once formed, quercetin quinone reacts preferentially with thiol groups compared with ascorbate ( 23 ). The quinone form of quercetin is only a poor substrate for NQO1 and although NQO1 is induced by quercetin, NQO1 does not provide protection from the effects of quercetin quinone ( 22 ).…”

“…Further, stabilization of Nrf2 or of Keap-1 by interaction with cysteine residues requires catechol groups ( 225 ). Methylation of one of the hydroxyl residues of quercetin prevents the formation of thiol adducts ( 131 ), but since 4′- O -methylquercetin induces HO-1 in HepG2 cells ( 272 ), this suggests that interaction of the catechol group with thiol residues on Keap-1 or Nrf2 is not the only mechanism of induction of ARE-controlled genes by flavonoids. When treated with 20 μ M quercetin, GSH concentration in HAEC transiently dropped by 20% and returned to baseline within 18 h. Since GSSG also decreased, this suggests that these changes were due to consumption of glutathione rather than thiol oxidation, and in support of this, quercetin glutathione conjugates were exported into the medium ( 132 ).…”