• This record comes from PubMed

The role of metallothionein in oxidative stress

. 2013 Mar 15 ; 14 (3) : 6044-66. [epub] 20130315

Status PubMed-not-MEDLINE Language English Country Switzerland Media electronic

Document type Journal Article

Free radicals are chemical particles containing one or more unpaired electrons, which may be part of the molecule. They cause the molecule to become highly reactive. The free radicals are also known to play a dual role in biological systems, as they can be either beneficial or harmful for living systems. It is clear that there are numerous mechanisms participating on the protection of a cell against free radicals. In this review, our attention is paid to metallothioneins (MTs) as small, cysteine-rich and heavy metal-binding proteins, which participate in an array of protective stress responses. The mechanism of the reaction of metallothioneins with oxidants and electrophilic compounds is discussed. Numerous reports indicate that MT protects cells from exposure to oxidants and electrophiles, which react readily with sulfhydryl groups. Moreover, MT plays a key role in regulation of zinc levels and distribution in the intracellular space. The connections between zinc, MT and cancer are highlighted.

See more in PubMed

Halliwell B., Gutteridge J.M.C. Oxygen free-radicals and iron in relation to biology and medicine—Some problems and concepts. Arch. Biochem. Biophys. 1986;246:501–514. PubMed

Cadenas E. Biochemistry of oxygen-toxicity. Annu. Rev. Biochem. 1989;58:79–110. PubMed

Valko M., Izakovic M., Mazur M., Rhodes C.J., Telser J. Role of oxygen radicals in DNA damage and cancer incidence. Mol. Cell. Biochem. 2004;266:37–56. PubMed

Poli G., Leonarduzzi G., Biasi F., Chiarpotto E. Oxidative stress and cell signalling. Curr. Med. Chem. 2004;11:1163–1182. PubMed

Halliwell B. Antioxidants in human health and disease. Annu. Rev. Nutr. 1996;16:33–50. PubMed

Gutteridge J.M.C., Halliwell B. Comments on review of free-radicals in biology and medicine. Free Radic. Biol. Med. 1992;12:93–95. PubMed

Niki E. Free radicals in biology and medicine: Good, unexpected, and uninvited friends. Free Radic. Biol. Med. 2010;49:S2.

Halliwell B., Gutteridge J.M.C. Free-Radicals in Biology and Medicine. Clarendon Press; Gloucestershire, UK: 1985.

Pacher P., Beckman J.S., Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol. Rev. 2007;87:315–424. PubMed PMC

Ramalingam M., Kim S.J. Reactive oxygen/nitrogen species and their functional correlations in neurodegenerative diseases. J. Neural Transm. 2012;119:891–910. PubMed

Pourova J., Kottova M., Voprsalova M., Pour M. Reactive oxygen and nitrogen species in normal physiological processes. Acta Physiol. 2010;198:15–35. PubMed

Vasak M. Advances in metallothionein structure and functions. J. Trace Elements Med Biol. 2005;19:13–17. PubMed

Henkel G., Krebs B. Metallothioneins: Zinc, cadmium, mercury, and copper thiolates and selenolates mimicking protein active site features—Structural aspects and biological implications. Chem. Rev. 2004;104:801–824. PubMed

Coyle P., Philcox J.C., Carey L.C., Rofe A.M. Metallothionein: The multipurpose protein. Cell. Mol. Life Sci. 2002;59:627–647. PubMed PMC

Margoshes M., Vallee B.L. A cadmium protein from equine kidney cortex. J. Am. Chem. Soc. 1957;79:4813–4814.

Kagi J.H.R., Schaffer A. Biochemistry of metallothionein. Biochemistry. 1988;27:8509–8515. PubMed

Romero-Isart N., Vasak M. Advances in the structure and chemistry of metallothioneins. J. Inorg. Biochem. 2002;88:388–396. PubMed

Davis S.R., Cousins R.J. Metallothionein expression in animals: A physiological perspective on function. J. Nutr. 2000;130:1085–1088. PubMed

Klaassen C.D., Liu J., Diwan B.A. Metallothionein protection of cadmium toxicity. Toxicol. Appl. Pharmacol. 2009;238:215–220. PubMed PMC

Templeton D.M., Cherian M.G. Toxicological significance of metallothionein. Methods Enzymol. 1991;205:11–24. PubMed

Kagi J.H.R. Overview of metallothionein. Methods Enzymol. 1991;205:613–626. PubMed

Shaw C.F., Savas M.M., Petering D.H. Ligand substitution and sulfhydryl reactivity of metallothionein. Methods Enzymol. 1991;205:401–414. PubMed

Karin M., Cathala G., Nguyenhuu M.C. Expression and regulation of a human metallothionein gene carried on an autonomously replicating shuttle vector. Proc. Natl. Acad. Sci. USA. 1983;80:4040–4044. PubMed PMC

Enger M.D., Tesmer J.G., Travis G.L., Barham S.S. Clonal variation of cadmium response in human-tumor cell-lines. Am. J. Phys. 1986;250:C256–C263. PubMed

Liu Y.P., Liu J., Iszard M.B., Andrews G.K., Palmiter R.D., Klaassen C.D. Transgenic mice that overexpress metallothionein-I are protected from cadmium lethality and hepatotoxicity. Toxicol. Appl. Pharmacol. 1995;135:222–228. PubMed

Masters B.A., Kelly E.J., Quaife C.J., Brinster R.L., Palmiter R.D. Targeted disruption of metallothionein-I and metallothionein-II genes increases sensitivity to cadmium. Proc. Natl. Acad. Sci. USA. 1994;91:584–588. PubMed PMC

Petrlova J., Potesil D., Mikelova R., Blastik O., Adam V., Trnkova L., Jelen F., Prusa R., Kukacka J., Kizek R. Attomole voltammetric determination of metallothionein. Electrochim. Acta. 2006;51:5112–5119.

Simpkins C.O. Metallothionein in human disease. Cell. Mol. Biol. 2000;46:465–488. PubMed

Hamer D.H. Metallothionein—An Overview. Mar. Environ. Res. 1988;24:171–171.

Masters B.A., Quaife C.J., Erickson J.C., Kelly E.J., Froelick G.J., Zambrowicz B.P., Brinster R.L., Palmiter R.D. Metallothionein-III is expressed in neurons that sequester zinc in synaptic vesicles. J. Neurosci. 1994;14:5844–5857. PubMed PMC

Moffatt P., Denizeau F. Metallothionein in physiological and physiopathological processes. Drug Metab. Rev. 1997;29:261–307. PubMed

Searle P.F., Davison B.L., Stuart G.W., Wilkie T.M., Norstedt G., Palmiter R.D. Regulation, linkage, and sequence of mouse metallothionein-I and metallothionein-II genes. Mol. Cell. Biol. 1984;4:1221–1230. PubMed PMC

Moffatt P., Seguin C. Expression of the gene encoding metallothionein-3 in organs of the reproductive system. DNA Cell. Biol. 1998;17:501–510. PubMed

Uchida Y., Takio K., Titani K., Ihara Y., Tomonaga M. The growth inhibitory factor that is deficient in the Alzheimers-disease brain is a 68-amino acid metallothionein-like protein. Neuron. 1991;7:337–347. PubMed

Quaife C.J., Findley S.D., Erickson J.C., Froelick G.J., Kelly E.J., Zambrowicz B.P., Palmiter R.D. Induction of a new metallothionein isoform (Mt-Iv) occurs during differentiation of stratified squamous epithelia. Biochemistry. 1994;33:7250–7259. PubMed

Moleirinho A., Carneiro J., Matthiesen R., Silva R.M., Amorim A., Azevedo L. Gains, losses and changes of function after gene duplication: Study of the metallothionein family. PLoS One. 2011;6:e18487. PubMed PMC

Vallee B.L. The function of metallothionein. Neurochem. Int. 1995;27:23–33. PubMed

Wong C.P., Ho E. Zinc and its role in age-related inflammation and immune dysfunction. Mol. Nutr. Food Res. 2012;56:77–87. PubMed

Chasapis C.T., Loutsidou A.C., Spiliopoulou C.A., Stefanidou M.E. Zinc and human health: An update. Arch. Toxicol. 2012;86:521–534. PubMed

Plum L.M., Rink L., Haase H. The essential toxin: Impact of zinc on human health. Int. J. Environ. Res. Public Health. 2010;7:1342–1365. PubMed PMC

Biswas S.K., Rahman I. Environmental toxicity, redox signaling and lung inflammation: The role of glutathione. Mol. Aspects Med. 2009;30:60–76. PubMed PMC

Franklin R.B., Costello L.C. The important role of the apoptotic effects of zinc in the development of cancers. J. Cell. Biochem. 2009;106:750–757. PubMed PMC

MacDonald R.S. The role of zinc in growth and cell proliferation. J. Nutr. 2000;130:1500S–1508S. PubMed

Prasad A.S. Zinc—An overview. Nutrition. 1995;11:93–99. PubMed

Oteiza P.I. Zinc and the modulation of redox homeostasis. Free Radic. Biol. Med. 2012;53:1748–1759. PubMed PMC

Costello L.C., Franklin R.B. Cytotoxic/tumor suppressor role of zinc for the treatment of cancer: An enigma and an opportunity. Expert Rev. Anticancer Ther. 2012;12:121–128. PubMed PMC

Carraway R.E., Dobner P.R. Zinc pyrithione induces ERK- and PKC-dependent necrosis distinct from TPEN-induced apoptosis in prostate cancer cells. Biochim. Biophys. Acta. 2012;1823:544–557. PubMed

Guo B.L., Yang M.W., Liang D., Yang L., Cao J.J., Zhang L. Cell apoptosis induced by zinc deficiency in osteoblastic MC3T3-E1 cells via a mitochondrial-mediated pathway. Mol. Cell. Biochem. 2012;361:209–216. PubMed

Kambe T., Yamaguchi-Iwai Y., Sasaki R., Nagao M. Overview of mammalian zinc transporters. Cell. Mol. Life Sci. 2004;61:49–68. PubMed PMC

Hogstrand C., Kille P., Nicholson R.I., Taylor K.M. Zinc transporters and cancer: A potential role for ZIP7 as a hub for tyrosine kinase activation. Trends Mol. Med. 2009;15:101–111. PubMed

Hathout Y., Fabris D., Fenselau C. Stoichiometry in zinc ion transfer from metallothionein to zinc finger peptides. Int. J. Mass Spectrom. 2001;204:1–6.

Costello L.C., Liu Y.Y., Franklin R.B., Kennedy M.C. Zinc inhibition of mitochondrial aconitase and its importance in citrate metabolism of prostate epithelial cells. J. Biol. Chem. 1997;272:28875–28881. PubMed

Coffey R.N.T., Watson R.W.G., Hegarty N.J., O'Neill A., Gibbons N., Brady H.R., Fitzpatrick J.M. Thiol-Mediated apoptosis in prostate carcinoma cells. Cancer. 2000;88:2092–2104. PubMed

Feng P., Liang J.Y., Li T.L., Guan Z.X., Zou J., Franklin R.B., Costello L.C. Zinc induces mitochondria apoptogenesis in prostate cells. Mol. Urol. 2000;4:31–36. PubMed

Costello L.C., Fenselau C.C., Franklin R.B. Evidence for operation of the direct zinc ligand exchange mechanism for trafficking, transport, and reactivity of zinc in mammalian cells. J. Inorg. Biochem. 2011;105:589–599. PubMed PMC

Vallee B.L., Falchuk K.H. The biochemical basis of zinc physiology. Physiol. Rev. 1993;73:79–118. PubMed

Gumulec J., Masarik M., Krizkova S., Adam V., Hubalek J., Hrabeta J., Eckschlager T., Stiborova M., Kizek R. Insight to Physiology and pathology of zinc(II) ions and their actions in breast and prostate carcinoma. Curr. Med. Chem. 2011;18:5041–5051. PubMed

Aimo L., Cherr G.N., Oteiza P.I. Low extracellular zinc increases neuronal oxidant production through nadph oxidase and nitric oxide synthase activation. Free Radic. Biol. Med. 2010;48:1577–1587. PubMed PMC

Kojima-Yuasa A., Umeda K., Olikita T., Kennedy D.O., Nishiguchi S., Matsui-Yuasa I. Role of reactive oxygen species in zinc deficiency-induced hepatic stellate cell activation. Free Radic. Biol. Med. 2005;39:631–640. PubMed

Kraus A., Roth H.P., Kirchgessner M. Supplementation with vitamin C, vitamin E or beta-carotene influences osmotic fragility and oxidative damage of erythrocytes of zinc-deficient rats. J. Nutr. 1997;127:1290–1296. PubMed

Oteiza P.I., Olin K.L., Fraga C.G., Keen C.L. Zinc-Deficiency causes oxidative damage to proteins, lipids and DNA in rat testes. J. Nutr. 1995;125:823–829. PubMed

Wang M.H., Yang F., Zhang X.Z., Zhao H.B., Wang Q.S., Pan Y.C. Comparative analysis of MTF-1 binding sites between human and mouse. Mamm. Genome. 2010;21:287–298. PubMed

Andrews G.K. Regulation of metallothionein gene expression by oxidative stress and metal ions. Biochem. Pharmacol. 2000;59:95–104. PubMed

Soltaninassab S.R., Sekhar K.R., Meredith M.J., Freeman M.L. Multi-faceted regulation of gamma-glutamylcysteine synthetase. J. Cell. Physiol. 2000;182:163–170. PubMed

Cortese M.M., Suschek C.V., Wetzel W., Kroncke K.D., Kolb-Bachofen V. Zinc protects endothelial cells from hydrogen peroxide via Nrf2-dependent stimulation of glutathione biosynthesis. Free Radic. Biol. Med. 2008;44:2002–2012. PubMed

Westbrook G.L., Mayer M.L. Micromolar concentrations of Zn2+ antagonize NMDA and GABA responses of hippocampal-neurons. Nature. 1987;328:640–643. PubMed

Maret W., Li Y. Coordination dynamics of zinc in proteins. Chem. Rev. 2009;109:4682–4707. PubMed

Zitka O., Kukacka J., Krizkova S., Huska D., Adam V., Masarik M., Prusa R., Kizek R. Matrix metalloproteinases. Curr. Med. Chem. 2010;17:3751–3768. PubMed

Yan W., Imanishi M., Futaki S., Sugiura Y. Alpha-Helical linker of an artificial 6-zinc finger peptide contributes to selective DNA binding to a discontinuous recognition sequence. Biochemistry. 2007;46:8517–8524. PubMed

Krishna S.S., Majumdar I., Grishin N.V. Structural classification of zinc fingers. Nucleic Acids Res. 2003;31:532–550. PubMed PMC

Posewitz M.C., Wilcox D.E. Properties of the SP1 zinc-finger-3 peptide-coordination chemistry, redox reactions, and metal-binding competition with metallothionein. Chem. Res. Toxicol. 1995;8:1020–1028. PubMed

Huang M., Shaw C.F., Petering D.H. Interprotein metal exchange between transcription factor IIIa and apo-metallothionein. J. Inorg. Biochem. 2004;98:639–648. PubMed PMC

CanoGauci D.F., Sarkar B. Reversible zinc exchange between metallothionein and the estrogen receptor zinc finger. FEBS Lett. 1996;386:1–4. PubMed

Zeng J., Heuchel R., Schaffner W., Kagi J.H.R. Thionein (apometallothionein) can modulate DNA-binding and transcriptional activation by zinc finger containing factor-SP1. FEBS Lett. 1991;279:310–312. PubMed

Zeng J., Vallee B.L., Kagi J.H.R. Zinc transfer from transcription factor-IIIA fingers to thionein clusters. Proc. Natl. Acad. Sci. USA. 1991;88:9984–9988. PubMed PMC

Maret W., Larsen K.S., Vallee B.L. Coordination dynamics of biological zinc “clusters” in metallothioneins and in the DNA-binding domain of the transcription factor Gal4. Proc. Natl. Acad. Sci. USA. 1997;94:2233–2237. PubMed PMC

Roesijadi G., Bogumil R., Vasak M., Kagi J.H.R. Modulation of DNA binding of a tramtrack zinc finger peptide by the metallothionein-thionein conjugate pair. J. Biol. Chem. 1998;273:17425–17432. PubMed

Kroncke K.D., Klotz L.O. Zinc fingers as biologic redox switches? Antioxid. Redox Signal. 2009;11:1015–1027. PubMed

Maret W. Metallothionein disulfide interactions, oxidative stress, and the mobilization of cellular zinc. Neurochem. Int. 1995;27:111–117. PubMed

Jacob C., Maret W., Vallee B.L. Control of zinc transfer between thionein, metallothionein, and zinc proteins. Proc. Natl. Acad. Sci. USA. 1998;95:3489–3494. PubMed PMC

Jiang L.J., Maret W., Vallee B.L. The glutathione redox couple modulates zinc transfer from metallothionein to zinc-depleted sorbitol dehydrogenase. Proc. Natl. Acad. Sci. USA. 1998;95:3483–3488. PubMed PMC

Maret W. Oxidative metal release from metallothionein via zinc thiol-disulfide interchange. Proc. Natl. Acad. Sci. USA. 1994;91:237–241. PubMed PMC

Kroncke K.D., Fehsel K., Schmidt T., Zenke F.T., Dasting I., Wesener J.R., Bettermann H., Breunig K.D., Kolbbachofen V. Nitric-oxide destroys zinc-sulfur clusters inducing zinc release from metallothionein and inhibition of the zinc finger-type yeast transcription activator LAC9. Biochem. Biophys. Res. Commun. 1994;200:1105–1110. PubMed

St Croix C.M., Wasserloos K.J., Dineley K.E., Reynolds I.J., Levitan E.S., Pitt B.R. Nitric oxide-induced changes in intracellular zinc homeostasis are mediated by metallothionein/thionein. Am. J. Physiol. 2002;282:L185–L192. PubMed

Spahl D.U., Berendji-Grun D., Suschek C.V., Kolb-Bachofen V., Kroncke K.D. Regulation of zinc homeostasis by inducible NO synthase-derived NO: Nuclear translocation and intranuclear metallothionein Zn2+ release. Proc. Natl. Acad. Sci. USA. 2003;100:13952–13957. PubMed PMC

Malaiyandi L.M., Dineley K.E., Reynolds I.J. Divergent consequences arise from metallothionein overexpression in astrocytes: Zinc buffering and oxidant-induced zinc release. Glia. 2004;45:346–353. PubMed

Pearce L.L., Gandley R.E., Han W.P., Wasserloos K., Stitt M., Kanai A.J., McLaughlin M.K., Pitt B.R., Levitan E.S. Role of metallothionein in nitric oxide signaling as revealed by a green fluorescent fusion protein. Proc. Natl. Acad. Sci. USA. 2000;97:477–482. PubMed PMC

Maret W. Zinc and sulfur: A critical biological partnership. Biochemistry. 2004;43:3301–3309. PubMed

Maret W., Vallee B.L. Thiolate ligands in metallothionein confer redox activity on zinc clusters. Proc. Natl. Acad. Sci. USA. 1998;95:3478–3482. PubMed PMC

Maret W. Redox biochemistry of mammalian metallothioneins. J. Biol. Inorg. Chem. 2011;16:1079–1086. PubMed

Cherian M.G., Jayasurya A., Bay B.H. Metallothioneins in human tumors and potential roles in carcinogenesis. Mutat. Res. 2003;533:201–209. PubMed

Ebadi M., Leuschen M.P., ElRefaey H., Hamada F.M., Rojas P. The antioxidant properties of zinc and metallothionein. Neurochem. Int. 1996;29:159–166. PubMed

Kang Y.J. Metallothionein redox cycle and function. Exp. Biol. Med. 2006;231:1459–1467. PubMed

Sato M., Bremner I. Oxygen free-radicals and metallothionein. Free Radic. Biol. Med. 1993;14:325–337. PubMed

Iszard M.B., Liu J., Klassen C.D. Effect of several metallothionein inducers on oxidative stress defense mechanisms in rats. Toxicology. 1995;104:25–33. PubMed

Aschner M., Conklin D.R., Yao C.P., Allen J.W., Tan K.H. Induction of astrocyte metallothioneins (MTs) by zinc confers resistance against the acute cytotoxic effects of methylmercury on cell swelling, Na+ uptake, and K+ release. Brain Res. 1998;813:254–261. PubMed

Namdarghanbari M., Wobig W., Krezoski S., Tabatabai N.M., Petering D.H. Mammalian metallothionein in toxicology, cancer, and cancer chemotherapy. J. Biol. Inorg. Chem. 2011;16:1087–1101. PubMed

Cai L., Koropatnick J., Cherian M.G. Metallothionein protects DNA from copper-induced but not iron-induced cleavage in vitro. Chem. Biol. Interact. 1995;96:143–155. PubMed

Shibuya K., Nishimura N., Suzuki J.S., Tohyama C., Naganuma A., Satoh M. Role of metallothionein as a protective factor against radiation carcinogenesis. J. Toxicol. Sci. 2008;33:651–655. PubMed

Schwarz M.A., Lazo J.S., Yalowich J.C., Allen W.P., Whitmore M., Bergonia H.A., Tzeng E., Billiar T.R., Robbins P.D., Lancaster J.R., et al. Metallothionein protects against the cytotoxic and DNA-damaging effects of nitric-oxide. Proc. Natl. Acad. Sci. USA. 1995;92:4452–4456. PubMed PMC

Kondo Y., Rusnak J.M., Hoyt D.G., Settineri C.E., Pitt B.R., Lazo J.S. Enhanced apoptosis in metallothionein null cells. Mol. Pharmacol. 1997;52:195–201. PubMed

Tao X., Zheng J.M., Xu A.M., Chen X.F., Zhang S.H. Downregulated expression of metallothionein and its clinicopathological significance in hepatocellular carcinoma. Hepatol. Res. 2007;37:820–827. PubMed

Fraker P.J., King L.E. A distinct role for apoptosis in the changes in lymphopoiesis and myelopoiesis created by deficiencies in zinc. FASEB J. 2001;15:2572–2578. PubMed

Mao J., Yu H.X., Wang C.J., Sun L.H., Jiang W., Zhang P.Z., Xiao Q.Y., Han D.B., Saiyin H., Zhu J.D., et al. Metallothionein MT1M is a tumor suppressor of human hepatocellular carcinomas. Carcinogenesis. 2012;33:2568–2577. PubMed

Yan D.W., Fan J.W., Yu Z.H., Li M.X., Wen Y.G., Li D.W., Zhou C.Z., Wang X.L., Wang Q., Tang H.M., et al. Downregulation of Metallothionein 1F, a putative oncosuppressor, by loss of heterozygosity in colon cancer tissue. Biochim. Biophys. Acta. 2012;1822:918–926. PubMed

Faller W.J., Rafferty M., Hegarty S., Gremel G., Ryan D., Fraga M.F., Esteller M., Dervan P.A., Gallagher W.M. Metallothionein 1E is methylated in malignant melanoma and increases sensitivity to cisplatin-induced apoptosis. Melanoma Res. 2010;20:392–400. PubMed

Takahashi S. Molecular functions of metallothionein and its role in hematological malignancies. J. Hematol. Oncol. 2012;5:1–8. PubMed PMC

Dutsch-Wicherek M., Sikora J., Tomaszewska R. The possible biological role of metallothionein in apoptosis. Front. Biosci. 2008;13:4029–4038. PubMed

McGee H.M., Woods G.M., Bennett B., Chung R.S. The two faces of metallothionein in carcinogenesis: Photoprotection against UVR-induced cancer and promotion of tumour survival. Photochem. Photobiol. Sci. 2010;9:586–596. PubMed

Chaabane W., User S.D., El-Gazzah M., Jaksik R., Sajjadi E., Rzeszowska-Wolny J., Los M.J. Autophagy, apoptosis, mitoptosis and necrosis: Interdependence between those pathways and effects on cancer. Arch. Immunol. Ther. Exp. 2013;61:43–58. PubMed

Ouyang L., Shi Z., Zhao S., Wang F.T., Zhou T.T., Liu B., Bao J.K. Programmed cell death pathways in cancer: A review of apoptosis, autophagy and programmed necrosis. Cell. Prolif. 2012;45:487–498. PubMed PMC

Nath R., Kumar D., Li T.M., Singal P.K. Metallothioneins, oxidative stress and the cardiovascular system. Toxicology. 2000;155:17–26. PubMed

Wyllie A.H. Apoptosis: An overview. Br. Med. Bull. 1997;53:451–465. PubMed

Thornberry N.A., Lazebnik Y. Caspases: Enemies within. Science. 1998;281:1312–1316. PubMed

Wyllie A.H., Bellamy C.O.C., Bubb V.J., Clarke A.R., Corbet S., Curtis L., Harrison D.J., Hooper M.L., Toft N., Webb S., et al. Apoptosis and carcinogenesis. Br. J. Cancer. 1999;80:34–37. PubMed

Dhawan D.K., Chadha V.D. Zinc: A promising agent in dietary chemoprevention of cancer. Indian J. Med. Res. 2010;132:676–682. PubMed PMC

Telford W.G., Fraker P.J. Preferential induction of apoptosis in mouse CD4(+)CD8(+)alphabeta- tcr(lo)CD3-epsilon(lo) thymocytes by zinc. J. Cell. Physiol. 1995;164:259–270. PubMed

Perry D.K., Smyth M.J., Stennicke H.R., Salvesen G.S., Duriez P., Poirier G.G., Hannun Y.A. Zinc is a potent inhibitor of the apoptotic protease, caspase-3—A novel target for zinc in the inhibition of apoptosis. J. Biol. Chem. 1997;272:18530–18533. PubMed

Stefanidou M., Maravelias C., Dona A., Spiliopoulou C. Zinc: A multipurpose trace element. Arch. Toxicol. 2006;80:1–9. PubMed

Seve M., Chimienti F., Favier A. Role of intracellular zinc in programmed cell death. Pathol. Biol. 2002;50:212–221. PubMed

Fan L.Z., Cherian M.G. Potential role of p53 on metallothionein induction in human epithelial breast cancer cells. Br. J. Cancer. 2002;87:1019–1026. PubMed PMC

Meplan C., Verhaegh G., Richard M.J., Hainaut P. Metal ions as regulators of the conformation and function of the tumour suppressor protein p53: Implications for carcinogenesis. Proc. Nutr. Soc. 1999;58:565–571. PubMed

Meplan C., Richard M.J., Hainaut P. Metalloregulation of the tumor suppressor protein p53: zinc mediates the renaturation of p53 after exposure to metal chelators in vitro and in intact cells. Oncogene. 2000;19:5227–5236. PubMed

Maret W., Jacob C., Vallee B.L., Fischer E.H. Inhibitory sites in enzymes: Zinc removal and reactivation by thionein. Proc. Natl. Acad. Sci. USA. 1999;96:1936–1940. PubMed PMC

Woo E.S., Kondo Y., Watkins S.C., Hoyt D.G., Lazo J.S. Nucleophilic distribution of metallothionein in human tumor cells. Exp. Cell. Res. 1996;224:365–371. PubMed

Sliwinska-Mosson M., Milnerowicz H., Rabczynski J., Milnerowicz S. Immunohistochemical localization of metallothionein and p53 protein in pancreatic serous cystadenomas. Arch. Immunol. Ther. Exp. 2009;57:295–301. PubMed

Cardoso S.V., Silveira J.B., Machado V.D., De-Paula A.M.B., Loyola A.M., de Aguiar M.C.F. Expression of metallothionein and p53 antigens are correlated in oral squamous cell carcinoma. Anticancer Res. 2009;29:1189–1193. PubMed

Baldwin A.S. Control of oncogenesis and cancer therapy resistance by the transcription factor NF-kappa B. J. Clin. Invest. 2001;107:241–246. PubMed PMC

Karin M., Cao Y.X., Greten F.R., Li Z.W. NF-Kappa B in cancer: From innocent bystander to major culprit. Nat. Rev. Cancer. 2002;2:301–310. PubMed

Wang C.Y., Mayo M.W., Korneluk R.G., Goeddel D.V., Baldwin A.S. NF-kappa B antiapoptosis: Induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science. 1998;281:1680–1683. PubMed

Wang C.Y., Guttridge D.C., Mayo M.W., Baldwin A.S. NF-kappa B induces expression of the Bcl-2 homologue A1/Bfl-1 to preferentially suppress chemotherapy-induced apoptosis. Mol. Cell. Biol. 1999;19:5923–5929. PubMed PMC

Wu M.X., Ao Z.H., Prasad K.V.S., Wu R.L., Schlossman S.F. IEX-1L, an apoptosis inhibitor involved in NF-kappa B-mediated cell survival. Science. 1998;281:998–1001. PubMed

Butcher H.L., Kennette W.A., Collins O., Zalups R.K., Koropatnick J. Metallothionein mediates the level and activity of nuclear factor kappa B in murine fibroblasts. J. Pharmacol. Exp. Therapeutics. 2004;310:589–598. PubMed

Kim C.H., Kim J.H., Lee J., Ahn Y.S. Zinc-Induced NF-kappa B inhibition can be modulated by changes in the intracellular metallothionein level. Toxicol. Appl. Pharmacol. 2003;190:189–196. PubMed

Abdel-Mageed A.B., Agrawal K.C. Activation of nuclear factor kappa B: Potential role in metallothionein-mediated mitogenic response. Cancer Res. 1998;58:2335–2338. PubMed

Wang C.Y., Cusack J.C., Liu R., Baldwin A.S. Control of inducible chemoresistance: Enhanced anti-tumor therapy through increased apoptosis by inhibition of NF-kappa B. Nat. Med. 1999;5:412–417. PubMed

Kanekiyo M., Itoh N., Kawasaki A., Tanaka J., Nakanishi T., Tanaka K. Zinc-induced activation of the human cytomegalovirus major immediate-early promoter is mediated by metallothionein and nuclear factor-kappa B. Toxicol. Appl. Pharmacol. 2001;173:146–153. PubMed

Thornalley P.J., Vasak M. Possible role for metallothionein in protection against radiation-induced oxidative stress—Kinetics and mechanism of its reaction with superoxide and hydroxyl radicals. Biochim. Biophys. Acta. 1985;827:36–44. PubMed

Abel J., Deruiter N. Inhibition of hydroxyl-radical-generated DNA-degradation by metallothionein. Toxicol. Lett. 1989;47:191–196. PubMed

Cai L., Klein J.B., Kang Y.J. Metallothionein inhibits peroxynitrite-induced DNA and lipoprotein damage. J. Biol. Chem. 2000;275:38957–38960. PubMed

Schwarz M.A., Lazo J.S., Yalowich J.C., Reynolds I., Kagan V.E., Tyurin V., Kim Y.M., Watkins S.C., Pitt B.R. Cytoplasmic metallothionein overexpression protects NIH 3T3 cells from tert-butyl hydroperoxide toxicity. J. Biol. Chem. 1994;269:15238–15243. PubMed

Du X.H., Yang C.L. Mechanism of gentamicin-nephrotoxicity in rats and the protective effect of zinc-induced metallothionein synthesis. Nephrol. Dial. Transplant. 1994;9:135–140. PubMed

Yang C.L., Du X.H., Zhao J.H., Chen W., Han Y.X. Zinc-Induced metallothionein synthesis could protect from gentamicin-nephrotoxicity in suspended proximal tubules of rats. Renal Fail. 1994;16:61–69. PubMed

Hart B.A., Eneman J.D., Gong Q., DurieuxLu C.C. Increased oxidant resistance of alveolar epithelial type II cells. Isolated from rats following repeated exposure to cadmium aerosols. Toxicol. Lett. 1995;81:131–139. PubMed

Satoh M., Kondo Y., Mita M., Nakagawa I., Naganuma A., Imura N. Prevention of carcinogenicity of anticancer drugs by metallothionein induction. Cancer Res. 1993;53:4767–4768. PubMed

Satoh M., Naganuma A., Imura N. Effect of preinduction of metallothionein on paraquat toxicity in mice. Arch. Toxicol. 1992;66:145–148. PubMed

Quesada A.R., Byrnes R.W., Krezoski S.O., Petering D.H. Direct reaction of H2O2 with sulfhydryl groups in HL-60 cells: Zinc-metallothionein and other sites. Arch. Biochem. Biophys. 1996;334:241–250. PubMed

Chubatsu L.S., Meneghini R. Metallothionein protects DNA from oxidative damage. Biochem. J. 1993;291:193–198. PubMed PMC

Banerjee D., Onosaka S., Cherian M.G. Immunohistochemical localization of metallothionein in cell-nucleus and cytoplasm of rat-liver and kidney. Toxicology. 1982;24:95–105. PubMed

Nagel W.W., Vallee B.L. Cell-Cycle regulation of metallothionein in human colonic-cancer cells. Proc. Natl. Acad. Sci. USA. 1995;92:579–583. PubMed PMC

Ghoshal K., Jacob S.T. Regulation of metallothionein gene expression. Prog. Nucl. Res. Mol. Biol. 2001;66:357–384. PubMed

Tsujikawa K., Imai T., Kakutani M., Kayamori Y., Mimura T., Otaki N., Kimura M., Fukuyama R., Shimizu N. Localization of metallothionein in nuclei of growing primary cultured adult-rat hepatocytes. FEBS Lett. 1991;283:239–242. PubMed

Takahashi Y., Ogra Y., Ibata K., Suzuki K.T. Role of metallothionein in the cell cycle: Protection against the retardation of cell proliferation by endogenous reactive oxygen species. J. Health Sci. 2004;50:154–158.

Takahashi Y., Ogra Y., Suzuki K.T. Synchronized generation of reactive oxygen species with the cell cycle. Life Sci. 2004;75:301–311. PubMed

Takahashi Y., Ogra Y., Suzuki K.T. Nuclear trafficking of metallothionein requires oxidation of a cytosolic partner. J. Cell. Physiol. 2005;202:563–569. PubMed

Ogra Y., Onishi S., Kajiwara A., Hara A., Suzuki K.T. Enhancement of nuclear localization of metallothionein by nitric oxide. J. Health Sci. 2008;54:339–342.

Eckschlager T., Adam V., Hrabeta J., Figova K., Kizek R. Metallothioneins and cancer. Curr. Protein Peptide Sci. 2009;10:360–375. PubMed

Sato M. Dose-Dependent increases in metallothionein synthesis in the lung and liver of paraquat-treated rats. Toxicol. Appl. Pharmacol. 1991;107:98–105. PubMed

Sato M., Sasaki M., Hojo H. Antioxidative roles of metallothionein and manganese superoxide-dismutase induced by tumor-necrosis-factor-alpha and interleukin-6. Arch. Biochem. Biophys. 1995;316:738–744. PubMed

Shiraishi N., Yamamoto H., Takeda Y., Kondoh S., Hayashi H., Hashimoto K., Aono K. Increased metallothionein content in rat-liver and kidney following X-irradiation. Toxicol. Appl. Pharmacol. 1986;85:128–134. PubMed

Koropatnick J., Leibbrandt M., Cherian M.G. Organ-specific metallothionein induction in mice by X-irradiation. Radiat. Res. 1989;119:356–365. PubMed

Shibuya K., Satoh M., Muraoka M., Watanabe Y., Oida M., Shimizu H. Induction of metallothionein synthesis in transplanted murine tumors by X-irradiation. Radiat. Res. 1995;143:54–57. PubMed

Matsubara J., Tajima Y., Karasawa M. Promotion of radioresistance by metallothionein induction prior to irradiation. Environ. Res. 1987;43:66–74. PubMed

Matsubara J. Metallothionein induction—A measure of radioprotective action. Health Phys. 1988;55:433–436. PubMed

Liu J., Kimler B.F., Liu Y.P., Klaassen C.D. Metallothionein-I transgenic mice are not protected from gamma-radiation. Toxicol. Lett. 1999;104:183–187. PubMed

Sun X.H., Zhou Z.X., Kang Y.J. Attenuation of doxorubicin chronic toxicity in metallothionein-overexpressing transgenic mouse heart. Cancer Res. 2001;61:3382–3387. PubMed

Kang Y.J., Li Y., Sun X.C., Sun X.H. Antiapoptotic effect and inhibition of ischemia/reperfusion-induced myocardial injury in metallothionein-overexpressing transigenic mice. Am. J. Pathol. 2003;163:1579–1586. PubMed PMC

Cai L., Wang J.X., Li Y., Sun X.H., Wang L.P., Zhou Z.X., Kang Y.J. Inhibition of superoxide generation and associated nitrosative damage is involved in metallothionein prevention of diabetic cardiomyopathy. Diabetes. 2005;54:1829–1837. PubMed

Wang L.P., Zhou Z.X., Saari J.T., Kang Y.J. Alcohol-Induced myocardial fibrosis in metallothionein-null mice—Prevention by zinc supplementation. Am. J. Pathol. 2005;167:337–344. PubMed PMC

Merten K.E., Feng W.K., Zhang L., Pierce W., Cai J., Klein J.B., Kang Y.J. Modulation of cytochrome c oxidase-Va is possibly involved in metallothionein protection from doxorubicin cardiotoxicity. J. Pharmacol. Exp. Ther. 2005;315:1314–1319. PubMed

Zhou G.H., Li X.K., Hein D.W., Xiang X.L., Marshall J.P., Prabhu S.D., Cai L. Metallothionein suppresses angiotensin II-Induced nicotinamide adenine dinucleotide phosphate oxidase activation, nitrosative stress, apoptosis, and pathological remodeling in the diabetic heart. J. Am. Coll. Cardiol. 2008;52:655–666. PubMed

Egli D., Yepiskoposyan H., Selvaraj A., Balamurugan K., Rajaram R., Simons A., Multhaup G., Mettler S., Vardanyan A., Georgiev O., et al. A family knockout of all four Drosophila metallothioneins reveals a central role in copper homeostasis and detoxification. Mol. Cell. Biol. 2006;26:2286–2296. PubMed PMC

Krizkova S., Ryvolova M., Hrabeta J., Adam V., Stiborova M., Eckschlager T., Kizek R. Metallothioneins and zinc in cancer diagnosis and therapy. Drug Metab. Rev. 2012;44:287–301. PubMed

Newest 20 citations...

See more in
Medvik | PubMed

New insights into the role of metallothioneins in obesity and diabetes

. 2025 Jul 14 ; () : . [epub] 20250714

Aberrant neurodevelopment in human iPS cell-derived models of Alexander disease

. 2025 Jan ; 73 (1) : 57-79. [epub] 20240923

Navigating the redox landscape: reactive oxygen species in regulation of cell cycle

. 2024 Dec ; 29 (1) : 2371173. [epub] 20240707

Antioxidant-related enzymes and peptides as biomarkers of metallic nanoparticles (eco)toxicity in the aquatic environment

. 2024 Sep ; 364 () : 142988. [epub] 20240803

Retrieval action of zinc and folic acid for the restoration of normal reproductive function in bisphenol-A exposed male albino mice

. 2022 Jun ; 67 (9) : 479-486. [epub] 20220608

Metallothionein and Superoxide Dismutase-Antioxidative Protein Status in Fullerene-Doxorubicin Delivery to MCF-7 Human Breast Cancer Cells

. 2018 Oct 20 ; 19 (10) : . [epub] 20181020

Comparative gene expression profiling of human metallothionein-3 up-regulation in neuroblastoma cells and its impact on susceptibility to cisplatin

. 2018 Jan 12 ; 9 (4) : 4427-4439. [epub] 20171216

Establishment of oral squamous cell carcinoma cell line and magnetic bead-based isolation and characterization of its CD90/CD44 subpopulations

. 2017 Sep 12 ; 8 (39) : 66254-66269. [epub] 20170803

Prognostic significance of the tumour-adjacent tissue in head and neck cancers

. 2015 Dec ; 36 (12) : 9929-39. [epub] 20150714

Fluorescence-tagged metallothionein with CdTe quantum dots analyzed by the chip-CE technique

. 2015 ; 17 (11) : 423. [epub] 20151028

Jacks of metal/metalloid chelation trade in plants-an overview

. 2015 ; 6 () : 192. [epub] 20150402

Find record

Citation metrics

Loading data ...

Archiving options

Loading data ...