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 µM) of cells with quercetin can lead to the same effect on metallothoinein as one higher concentration treatment (100 µM). 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.
Similar content being viewed by others
References
E. Middleton, Jr. and C. Kandaswami, The importance of plant flavonoids on mammalian biology: implications for immunity, inflammation and cancer, in The Flavonoids: Advances in Research since 1986, J. B. Harborne, ed., Chapman & Hall, London, pp. 619–652 (1993).
S.-M. Kuo, Dietary flavonoid and cancer prevention: evidence and potential mechanism, Crit. Rev. Oncogen. 8, 47–69 (1997).
D. Goodman-Gruen and D. Kritz-Silverstein, Usual dietary isoflavone intake is associated with cardiovascular disease risk factors in postmenopausal women, J. Nutr. 131, 1202–1206 (2001).
B. A. Masters, E. J. Kelly, C. J. Quaife, R. L. Brinster, and R. D. Palmiter, Targeted disruption of metallothionein I and II genes increases sensitivity to cadmium, Proc. Natl. Acad. Sci. USA 91, 584–588 (1994).
H. Zheng, J. Liu, Y. Liu, and C. D. Klaassen, Hepatocytes from metallothionein-I and II knock-out mice are sensitive to cadmium and tert-butylhydroperoxide-induced cytotoxicity, Toxicol. Lett. 87, 139–145 (1996).
M. Satoh, N. Nishimura, Y. Kanayama, A. Naganuma, T. Suzuki, and C. Tohyama, Enhanced renal toxicity by inorganic mercury in metallothionein-null mice, J. Pharmacol. Exp. Ther. 283, 1529–1533 (1997).
G. J. Brewer, Interaction of zinc and molybdenum with copper in therapy of Wilson’s disease, Nutrition 11(Suppl. 1), 114–116 (1995).
S.-M. Kuo, P. S. Leavitt, and C.-P. Lin, Interaction of dietary flavonoids with trace metal ions and the effect on metallothionein level, Biol. Trace Element Res. 62, 135–153 (1998).
S. Kameoka, P. Leavitt, C. Chang, and S.-M. Kuo, Expression of antioxidant proteins in human intestinal cells treated with dietary flavonoids, Cancer Lett. 146, 161–167 (1999).
S.-M. Kuo and P. S. Leavitt, Genistein increases metallothionein expression in human intestinal cells, Biochem. Cell Biol. 77, 79–88 (1999).
S.-M. Kuo, Antiproliferative potency of structurally distinct dietary flavonoids on human colon cancer cells, Cancer Lett. 110, 41–48 (1996).
M. M. Bradford, A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding, Anal. Biochem. 72, 248–254 (1976).
A. Haslinger and M. Karin, Upstream promoter element of the human metallothionein-IIA gene can act like an enhancer element, Proc. Natl. Acad. Sci. USA 82, 8572–8576 (1985).
C. Sadhu and L. Gedamu, Regulation of human metallothionein genes. Differential expression of MTI-F, MTI-G, and MTII-A genes in the hepatoblastoma cell line (HepG2), J. Biol. Chem. 263, 2679–2684 (1988).
N. Jahroudi, R. Foster, J. Price-Haughey, G. Beitel, and L. Gedamu, Cell-type specific and differential regulation of the human metallothionein genes, J. Biol. Chem. 265, 6505–6511 (1990).
A. Rahman, F. Fazal, J. Greensill, K. Ainley, J. H. Parish, and S. M. Hadi, Strand scission in DNA induced by dietary flavonoids: role of Cu(I) and oxygen free radicals and biological consequences of scission, Mol. Cell. Biochem. 111, 3–9 (1992).
M. S. Ahmad, F. Fazal, A. Rahman, S. M. Hadi, and J. H. Parish, Activities of flavonoids for the cleavage of DNA in the presence of Cu(II): correlation with generation of active oxygen species, Carcinogenesis 13, 605–608 (1992).
J. E. Brown, H. Khodr, R. C. Hider, and C. A. Rice-Evans, Structural dependence of flavonoid interactions with Cu+2 ions: implications for their antioxidant properties, Biochem. J. 330, 1173–1178 (1998).
A. Blais, S. Lecoeur, G. Milhaud, D. Tomé, and M. Kolf-Clauw, Cadmium uptake and transepithelial transport in control and long-term exposed Caco-2 cells: the role of metallothionein, Toxicol. Appl. Pharmacol. 160, 76–85 (1999).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Kuo, SM., Huang, CT., Blum, P. et al. Quercetin cumulatively enhances copper induction of metallothionein in intestinal cells. Biol Trace Elem Res 84, 1–10 (2001). https://doi.org/10.1385/BTER:84:1-3:001
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1385/BTER:84:1-3:001