Quercetin Cumulatively Enhances Copper Induction of Metallothionein in Intestinal Cells

Abstract

Wilson's disease, a genetic copper-overload condition, is currently treated with zinc because of the ability of zinc to induce metallothionein. We are interested in nonmetal chemicals that may alter intestinal copper metabolism and thus help to alleviate copper toxicity. Previously, we have shown that quercetin, a dietary flavonoid, can chelate copper. This study further examined the interaction of quercetin and copper in intestinal epithelial cells. We found that quercetin enhanced metallothoinein induction by copper and the effect was dose dependent. Quercetin also exerted a cumulative effect after repeated exposure. Repeated low-dose treatment (3-10 microM) of cells with quercetin can lead to the same effect on metallothoinein as one higher concentration treatment (100 microM). This property of quercetin is distinct from its chemical interaction with copper, but both can contribute to a reduction of copper toxicity. Among other flavonoids tested, two other copper chelators, catechin and rutin, did not increase copper induction of metallothionein, whereas genistein, an isoflavone that does not interact with copper chemically, increased copper induction of metallothionein. The effect of quercetin on copper metabolism is unique. Quercetin decreased zinc-stimulated metallothionein expression and had no effect on the cadmium induction of metallothionein. The clinical application of our observation needs to be explored.

Research Communication: Flavonoid Structure Affects the Inhibition of Lipid Peroxidation in Caco-2 Intestinal Cells at Physiological Concentrations

“…Although some flavonoids have the iron-chelating property noted earier (17,(27)(28)(29), these experiments were carried out with higher concentration ratios of flavonoids to iron. In the current study, the iron concentration was 3-to 300-fold that of the flavonoids.…”

“…Cell membranes are permeable to flavonoids (10 -12). In addition, cellular retention of quercetin was demonstrated in our previous fluorescence imaging and gene expression experiments (13,14,17). A recent study on oxidative DNA damage reported an antioxidant effect of (-)-epigallocatechin gallate (EGCG) after extracellular EGCG was removed.…”

Zinc Ionophore Activity of Quercetin and Epigallocatechin-gallate: From Hepa 1-6 Cells to a Liposome Model

“…26 Early in vitro studies showed that, in human intestinal Caco-2 cells, genistein enhanced the expression of MT, here regarded as an antioxidant enzyme, 27 while QCT increased the copper-induced expression of MT. 28 More recently, QCT was shown to enhance zinc uptake by Caco-2 cells, increasing total zinc accumulation and MT expression. 29 In contrast, grape seed flavonoids, produced a reduction in apical zinc uptake in Caco-2 cells, similar to that produced by phytate, whereas EGCG did not alter zinc absorption.…”

Dietary catechins and procyanidins modulate zinc homeostasis in human HepG2 cells

“…For instance, in human intestinal Caco-2 cells, genistein enhances expression of MT, whereas quercetin has the opposite effect, albeit enhances copper induction of MT [38][39][40]. Also, long-term consumption of flavonoids may affect mineral status, and for instance, iron, copper and zinc levels are diminished in the liver of rats fed with rutin and baicalin [41].…”