Protein Information

Name metallothionein (protein family or complex)
Synonyms Metallothionein; Metallothioneins

Compound Information

Name copper sulfate
CAS sulfuric acid copper(2+) salt (1:1)

Reference List

PubMed Abstract RScore(About this table)
2846542 Butt TR, Khan MI, Marsh J, Ecker DJ, Crooke ST: Ubiquitin-metallothionein fusion protein expression in yeast. J Biol Chem. 1988 Nov 5;263(31):16364-71.

5(0,0,0,5) Details
18068524 Boldrin F, Santovito G, Formigari A, Bisharyan Y, Cassidy-Hanley D, Clark TG, Piccinni E: MTT2, a copper-inducible metallothionein gene from Tetrahymena thermophila. Comp Biochem Physiol C Toxicol Pharmacol. 2008 Mar;147(2):232-40. Epub 2007 Oct 25.

3(0,0,0,3) Details
2318858 Mehra RK, Garey JR, Winge DR: Selective and tandem amplification of a member of the metallothionein gene family in Candida glabrata. J Biol Chem. 1990 Apr 15;265(11):6369-75.

Strains of C. glabrata highly resistant to copper salts were obtained by repeated culturing of wild-type isolates in medium containing increasing concentrations of copper sulfate.
3(0,0,0,3) Details
11212915 Averbeck NB, Borghouts C, Hamann A, Specke V, Osiewacz HD: Molecular control of copper homeostasis in filamentous fungi: increased expression of a metallothionein gene during aging of Podospora anserina. Mol Gen Genet. 2001 Jan;264(5):604-12.

3(0,0,0,3) Details
8128500 Stephenson GF, Chan HM, Cherian MG: Copper-metallothionein from the toxic milk mutant mouse enhances lipid peroxidation initiated by an organic hydroperoxide. Toxicol Appl Pharmacol. 1994 Mar;125(1):90-6.

Addition of copper sulfate at high concentrations (100 microM) also increased t-BHP induced LP, but the enhancement was less pronounced than observed with Cu-MT addition.
3(0,0,0,3) Details
12680702 Mahboobi H, Viarengo A, Colangelo D, Osella D: Effect of metal-based anticancer drugs on wild type and metallothionein null cell lines. Biometals. 2003 Sep;16(3):403-9.

2(0,0,0,2) Details
19003289 Valle MA, Kester MB, Burns AL, Marx SJ, Spiegel AM, Shiloach J: Production and purification of human menin from Drosophila melanogaster S2 cells using stirred tank reactor. Cytotechnology. 2001 Mar;35(2):127-35.

Protein expression was achieved after inducing the metallothionein promoter by adding copper sulfate to cells growing in suspension in a stirred-tank reactor.
6(0,0,1,1) Details
8668123 Strain J, Culotta VC: Copper ions and the regulation of Saccharomyces cerevisiae metallothionein genes under aerobic and anaerobic conditions. Mol Gen Genet. 1996 May 23;251(2):139-45.

6(0,0,0,6) Details
9325024 Vincent R, Goegan P, Johnson G, Brook JR, Kumarathasan P, Bouthillier L, Burnett RT: Regulation of promoter-CAT stress genes in HepG2 cells by suspensions of particles from ambient air. Fundam Appl Toxicol. 1997 Sep;39(1):18-32.

Induction of the CAT genes was verified with benzo [a] pyrene (CYP1A1, cytochrome P450 1A1 promoter; GSTYa, glutathione transferase subunit Ya promoter; XRE, xenobiotic response element), cadmium sulfate, and copper sulfate (HMTIIa, metallothionein IIa promoter; HSP70, heat shock protein 70 promoter).
6(0,0,1,1) Details
14511662 Ohashi K, Kajiya K, Inaba S, Hasegawa T, Seko Y, Furuchi T, Naganuma A: Copper (II) protects yeast against the toxicity of cisplatin independently of the induction of metallothionein and the inhibition of platinum uptake. Biochem Biophys Res Commun. 2003 Oct 10;310(1):148-52.

We have made the unexpected discovery that copper sulfate protects Saccharomyces cerevisiae from the toxic effects of cisplatin.
5(0,0,0,5) Details
1783602 Hatayama T, Tsukimi Y, Wakatsuki T, Kitamura T, Imahara H: Different induction of 70,000-Da heat shock protein and metallothionein in HeLa cells by copper. J Biochem. 1991 Nov;110(5):726-31.

5(0,0,0,5) Details
9114495 Wu CC, Fallon AM: Evaluation of a heterologous metallothionein gene promoter in transfected mosquito cells. Comp Biochem Physiol B Biochem Mol Biol. 1997 Mar;116(3):353-8.

3(0,0,0,3) Details
10816730 Okuyama M, Kobayashi Y, Inouhe M, Tohoyama H, Joho M: Effect of some heavy metal ions on copper-induced metallothionein synthesis in the yeast Saccharomyces cerevisiae. Biometals. 1999 Dec;12(4):307-14.

2(0,0,0,2) Details
19410293 Calisi A, Lionetto MG, Schettino T: Pollutant-induced alterations of granulocyte morphology in the earthworm Eisenia foetida. Ecotoxicol Environ Saf. 2009 Jul;72(5):1369-77. Epub 2009 May 2.

Results showed consistent enlargement of earthworm granulocytes induced by exposure to either copper sulfate or methiocarb.
In order to verify the applicability of morphometric granulocyte alteration, a battery of standardized biomarkers such as lysosomal membrane stability, metallothionein induction, or acetylcholinesterase (AChE) inhibition were also determined.
1(0,0,0,1) Details
15296447 Lim HJ, Kim YK, Hwang DS, Cha HJ: Expression of functional human transferrin in stably transfected Drosophila S2 cells. Biotechnol Prog. 2004 Jul-Aug;20(4):1192-7.

Here, a plasmid encoding the hTf gene fused with a hexahistidine (His6) epitope tag under Drosophila metallothionein promoter (pMT) was stably transfected into Drosophila melanogaster S2 cells as a nonlytic plasmid-based system.
Following 3 days of copper sulfate induction, transfected S2 cells were found to secrete hTf into serum-free culture medium at a competitively high expression level of 40.8 microg/mL, producing 6.8 microg/mL/day in a 150-mL spinner flask culture.
1(0,0,0,1) Details
19003014 Santos MG, Jorge SA, Brillet K, Pereira CA: Improving heterologous protein expression in transfected Drosophila S2 cells as assessed by EGFP expression. Cytotechnology. 2007 May;54(1):15-24. Epub 2007 Mar 20.

Drosophila melanogaster S2 cells were co-transfected with plasmid vectors containing the enhanced green fluorescent protein gene (EGFP), under the control of metallothionein promoter (pMt), and the hygromycin selection gene, in view of establishing parameters for optimized gene expression.
A protocol of transfection was worked out, leading after hygromycin selection, to approximately 90% of S2MtEGFP fluorescent cells at day 5 after copper sulfate (CuSO (4)) induction.
1(0,0,0,1) Details
2188656 Fujita VS, Thiele DJ, Coon MJ: Expression of alcohol-inducible rabbit liver cytochrome P-450 3a (P-450IIE1) in Saccharomyces cerevisiae with the copper-inducible CUP1 promoter. DNA Cell Biol. 1990 Mar;9(2):111-8.


The expression of the cDNA for alcohol-inducible rabbit liver microsomal cytochrome P-450 form 3a (P450IIE1) in Saccharomyces cerevisiae, with the use of the copper-inducible yeast metallothionein (CUP1) promoter and the ADH1 promoter, is described.
1(0,0,0,1) Details
17963934 Kim KR, Kim YK, Cha HJ: Recombinant baculovirus-based multiple protein expression platform for Drosophila S2 cell culture. J Biotechnol. 2008 Jan 1;133(1):116-22. Epub 2007 Sep 21.

Based on the fact that baculovirus cannot replicate in nonpermissive Drosophila melanogaster Schneider line 2 (S2) cells, S2 cells that stably express human erythropoietin (hEPO) under the control of the S2-derived inducible metallothionein (MT) promoter were infected with three types of recombinant baculoviruses, each of which expressed a different fluorescent protein gene under the control of MT promoter.
Addition of copper sulfate as an inducer to infected, stably transfected S2 cells resulted in simultaneous expression of hEPO and three fluorescent proteins.
1(0,0,0,1) Details
8368941 Hirano S, Ebihara H, Sakai S, Kodama N, Suzuki KT: Pulmonary clearance and toxicity of intratracheally instilled cupric oxide in rats. Arch Toxicol. 1993;67(5):312-7.


Copper binding metallothionein (MT) was induced in a dose-dependent manner and detected at 12 h to 3 days post-instillation.
1(0,0,0,1) Details
20213433 Sampaio FG, de Lima Boijink C, Dos Santos LR, Oba ET, Kalinin AL, Rantin FT: The combined effect of copper and low pH on antioxidant defenses and biochemical parameters in neotropical fish pacu, Piaractus mesopotamicus (Holmberg, 1887). Ecotoxicology. 2010 Mar 6.

Copper sulfate is widely used in aquaculture.
Exposure to 0.4Cu and 0.4CupH resulted in a reduction in the Na (+)/K (+)-ATPase activity and an increase in metallothionein (MT) in the gills.
1(0,0,0,1) Details
15555945 Prosise WW, Yarosh-Tomaine T, Lozewski Z, Ingram RN, Zou J, Liu JJ, Zhu F, Taremi SS, Le HV, Wang W: Protease domain of human ADAM33 produced by Drosophila S2 cells. Protein Expr Purif. 2004 Dec;38(2):292-301.


On the other hand, similar constructs could be expressed, processed, and secreted by Drosophila S2 cells using a variety of constitutive (actin, pAc5.1) or inducible (metallothionein, PMT) promoters and leader sequences (e.g., native and BiP).
1(0,0,0,1) Details
9119067 Schafer HJ, Greiner S, Rausch T, Haag-Kerwer A: In seedlings of the heavy metal accumulator Brassica juncea Cu2+ differentially affects transcript amounts for gamma-glutamylcysteine synthetase (gamma-ECS) and metallothionein (MT2). FEBS Lett. 1997 Mar 10;404(2-3):216-20.

1(0,0,0,1) Details
16597887 Miller NS, Dick JD, Merz WG: Phenotypic switching in Candida lusitaniae on copper sulfate indicator agar: association with amphotericin B resistance and filamentation. J Clin Microbiol. 2006 Apr;44(4):1536-9.

Detection of PS on YPD-CuSO (4) is also similar to that in Candida glabrata, and we hypothesize that this is due to similarities in metallothionein gene expression.
1(0,0,0,1) Details
2956123 Huber M, Lerch K: The influence of copper on the induction of tyrosinase and laccase in Neurospora crassa. FEBS Lett. 1987 Jul 27;219(2):335-8.


This suggests the existence of a copper-storage protein for which metallothionein is a likely candidate.
1(0,0,0,1) Details
3887570 Hamer DH, Thiele DJ, Lemontt JE: Function and autoregulation of yeast copperthionein. Science. 1985 May 10;228(4700):685-90.


The CUP1 gene of yeast encodes a small, metallothionein-like protein that binds to and is inducible by copper.
1(0,0,0,1) Details
18528910 Yasokawa D, Murata S, Kitagawa E, Iwahashi Y, Nakagawa R, Hashido T, Iwahashi H: Mechanisms of copper toxicity in Saccharomyces cerevisiae determined by microarray analysis. Environ Toxicol. 2008 Oct;23(5):599-606.


Copper metallothionein CUP1-1 and CUP1-2 were induced more than 20-fold.
1(0,0,0,1) Details
7843131 Romeu-Moreno A, Aguilar C, Arola L, Mas A: Respiratory toxicity of copper. . Environ Health Perspect. 1994 Sep;102 Suppl 3:339-40.

Respiratory toxicity of copper was tested in Wistar rats by spraying copper sulfate (330 g/l spray) for daily periods of 1 hr in a self-contained chamber for up to 10 days.
After exposure, Cu and Zn were basically associated with a low-molecular-weight component, which eluted as metallothionein in the postmicrosomal fractions.
1(0,0,0,1) Details
16025538 Kim YK, Shin HS, Tomiya N, Lee YC, Betenbaugh MJ, Cha HJ: Production and N-glycan analysis of secreted human erythropoietin glycoprotein in stably transfected Drosophila S2 cells. Biotechnol Bioeng. 2005 Nov 20;92(4):452-61.

Here, a plasmid encoding the human erythropoietin (hEPO) gene fused with a hexahistidine (His (6)) tag under the control of the Drosophila metallothionein (MT) promoter was stably transfected into Drosophila S2 cells.
After copper sulfate induction, transfected S2 cells were found to secrete hEPO with a maximum expression level of 18 mg/L and a secretion efficiency near 98%.
1(0,0,0,1) Details
18533248 Almeida DV, Trindade GS, Geracitano LA, Barros DM, Monserrat JM, Marins LF: Initial results in the development of a reporter cell line for toxicology studies at gene expression level: activation of the electrophile-responsive element by copper and methyl parathion. Mar Environ Res. 2008 Jul;66(1):158-60. Epub 2008 Mar 8.

In order to evaluate the molecular response triggered by these pollutants, a stable cell line was produced, which carries a transgene comprised of the green fluorescent protein (GFP) reporter gene under transcriptional control of the mouse glutathione-S-transferase (gst1) electrophile-responsive element fused to the mouse metallothionein (mt1) minimal promoter.
EpREmt-GFP HTC cells were treated with 0.002 mg L (-1), 0.02 mg L (-1), 0.2 mg L (-1) and 2 mg L (-1) copper sulfate and 0.001 mg L (-1), 0.01 mg L (-1), 0.1 mg L (-1) and 1 mg L (-1) methyl parathion for 48 h.
1(0,0,0,1) Details
12963349 Perret BG, Wagner R, Lecat S, Brillet K, Rabut G, Bucher B, Pattus F: Expression of EGFP-amino-tagged human mu opioid receptor in Drosophila Schneider 2 cells: a potential expression system for large-scale production of G-protein coupled receptors. Protein Expr Purif. 2003 Sep;31(1):123-32.


The G-protein coupled receptor (GPCR) human mu opioid receptor (hMOR) fused to the carboxy-terminus of the enhanced green fluorescent protein (EGFP) has been successfully and stably expressed in Drosophila Schneider 2 cells under the control of an inducible metallothionein promoter.
1(0,0,0,1) Details
10940034 Riggle PJ, Kumamoto CA: Role of a Candida albicans P1-type ATPase in resistance to copper and silver ion toxicity. J Bacteriol. 2000 Sep;182(17):4899-905.


To identify Candida albicans genes that are involved in resistance to copper ion toxicity, a library containing inserts of C. albicans genomic DNA was used to complement the copper sensitivity phenotype of a Saccharomyces cerevisiae cup1Delta strain that is unable to produce Cup1p, a metallothionein (MT) responsible for high-level copper ion resistance.
1(0,0,0,1) Details
18987288 Craig PM, Galus M, Wood CM, McClelland GB: Dietary iron alters waterborne copper-induced gene expression in soft water acclimated zebrafish (Danio rerio). Am J Physiol Regul Integr Comp Physiol. 2009 Feb;296(2):R362-73. Epub 2008 Nov 5.


Additionally, we examined metallothionein 1 and 2 (MT1 and MT2), which indicated that MT2 is more responsive to Cu.
1(0,0,0,1) Details
2203342 Lu C, Yang YF, Ohashi H, Walfish PG: In vivo expression of rat liver c-erbA beta thyroid hormone receptor in yeast (Saccharomyces cerevisiae). Biochem Biophys Res Commun. 1990 Aug 31;171(1):138-42.

To study thyroid hormone receptor (TR), we developed an in vivo expression system in yeast by using a copper-responsive yeast metallothionein promoter and ubiquitin-fusion protein technology.
The [125I] T3 binding activities to yeast extracts were significantly correlated with the added copper sulfate into the medium.
1(0,0,0,1) Details
17728190 Garcia Sampaio F, de Lima Boijink C, Tie Oba E, Romagueira Bichara dos Santos L, Lucia Kalinin A, Tadeu Rantin F: Antioxidant defenses and biochemical changes in pacu (Piaractus mesopotamicus) in response to single and combined copper and hypoxia exposure. Comp Biochem Physiol C Toxicol Pharmacol. 2008 Jan;147(1):43-51. Epub 2007 Aug 1.


Metallothionein concentration in gills increased under combined-factors.
1(0,0,0,1) Details
7533712 Lin SL, Wu L: Effects of copper concentration on mineral nutrient uptake and copper accumulation in protein of copper-tolerant and nontolerant Lotus purshianus L. Ecotoxicol Environ Saf. 1994 Nov;29(2):214-28.

This pattern of amino acid composition is different from the amino acid composition of the phytochelatin metallothionein-like proteins found in copper-tolerant plants which are very high in cysteine.(ABSTRACT TRUNCATED AT 400 WORDS)
Plants were grown from seeds for a period of 24 days in a modified Hoagland nutrient solution culture supplemented with 3, 6, and 10 microM copper as copper sulfate.
1(0,0,0,1) Details
3192135 Kurisaki E, Kuroda Y, Sato M: Copper-binding protein in acute copper poisoning. Forensic Sci Int. 1988 Jul-Aug;38(1-2):3-11.


This paper presents a suicide case of copper sulfate ingestion.
0(0,0,0,0) Details
7948889 Foley RC, Singh KB: Isolation of a Vicia faba metallothionein-like gene: expression in foliar trichomes. Plant Mol Biol. 1994 Oct;26(1):435-44.

2(0,0,0,2) Details
18356017 Santon A, Formigari A, Irato P: The influence of metallothionein on exposure to metals: an in vitro study on cellular models. Toxicol In Vitro. 2008 Jun;22(4):980-7. Epub 2008 Feb 13.

2(0,0,0,2) Details
10639459 Lachke SA, Srikantha T, Tsai LK, Daniels K, Soll DR: Phenotypic switching in Candida glabrata involves phase-specific regulation of the metallothionein gene MT-II and the newly discovered hemolysin gene HLP. Infect Immun. 2000 Feb;68(2):884-95.

2(0,0,0,2) Details
1567201 Brouwer M, Schlenk D, Ringwood AH, Brouwer-Hoexum T: Metal-specific induction of metallothionein isoforms in the blue crab Callinectes sapidus in response to single- and mixed-metal exposure. Arch Biochem Biophys. 1992 May 1;294(2):461-8.

2(0,0,0,2) Details
14990219 dos Santos Carvalho C, de Araujo HS, Fernandes MN: Hepatic metallothionein in a teleost (Prochilodus scrofa) exposed to copper at pH 4.5 and pH 8.0. Comp Biochem Physiol B Biochem Mol Biol. 2004 Feb;137(2):225-34.

2(0,0,0,2) Details
19618744 Stolyar OB, Myhayliv RL, Mischuk OV: The concentration-specific response of metallothioneins in copper-loading freshwater bivalve Anodonta cygnea. Ukr Biokhim Zh. 2005;77(6):68-72.

2(0,0,0,2) Details
2584191 Mehra RK, Garey JR, Butt TR, Gray WR, Winge DR: Candida glabrata metallothioneins. J Biol Chem. 1989 Nov 25;264(33):19747-53.

The concentrations of MT-II mRNA appeared to be higher than that of MT-I mRNA at all concentrations of copper sulfate tested.
2(0,0,0,2) Details
18779161 Ban QY, Liu GF, Wang YC, Zhang DW, Jiang LL: [Cloning and expression of a novel metallothionein gene LbMT2 from Limonium bicolor]. Yi Chuan. 2008 Aug;30(8):1075-82.

2(0,0,0,2) Details
16221516 Suntres ZE, Lui EM: Prooxidative effect of copper--metallothionein in the acute cytotoxicity of hydrogen peroxide in Ehrlich ascites tumour cells. Toxicology. 2006 Jan 16;217(2-3):155-68. Epub 2005 Oct 10.

2(0,0,0,2) Details
12549029 Lin Z, Ma G, Li F, Shu J, Chang L: [Isolation, purification and identification of metallothionein from strain BD102 of Hansenula anomala]. Wei Sheng Wu Xue Bao. 2001 Apr;41(2):216-22.

2(0,0,0,2) Details
1890621 Suntres ZE, Lui EM: Age-related differences in iron-nitrilotriacetate hepatotoxicity in the guinea pig: role of copper metallothionein. J Pharmacol Exp Ther. 1991 Sep;258(3):797-806.

2(0,0,0,2) Details
9440242 Schlenk D, Wolford L, Chelius M, Steevens J, Chan KM: Effect of arsenite, arsenate, and the herbicide monosodium methyl arsonate (MSMA) on hepatic metallothionein expression and lipid peroxidation in channel catfish. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol. 1997 Oct;118(2):177-83.

2(0,0,0,2) Details
1339367 Mehra RK, Thorvaldsen JL, Macreadie IG, Winge DR: Disruption analysis of metallothionein-encoding genes in Candida glabrata. Gene. 1992 May 1;114(1):75-80.

2(0,0,0,2) Details
2267662 Hirano S, Sakai S, Ebihara H, Kodama N, Suzuki KT: Metabolism and pulmonary toxicity of intratracheally instilled cupric sulfate in rats. Toxicology. 1990 Dec 3;64(3):223-33.


We have investigated time-course and dose-related changes in Cu contents, the production of metallothionein (MT) and inflammatory responses in the rat lung following intratracheal instillation of cupric sulfate (CuSO4).
1(0,0,0,1) Details
1838130 Lerch K: Purification of Neurospora crassa copper-metallothionein. Methods Enzymol. 1991;205:278-83.

1(0,0,0,1) Details
12213913 Lachke SA, Joly S, Daniels K, Soll DR: Phenotypic switching and filamentation in Candida glabrata. Microbiology. 2002 Sep;148(Pt 9):2661-74.


These phenotypes also differ in a graded fashion in the level of expression of the metallothionein gene MTII (Wh vDB), the frequency of switching (Wh> LB> DB> vDB) and colouration on phloxine B-containing agar (Wh> LB> DB> vDB).
1(0,0,0,1) Details
1783126 Scarino ML, Poverini R, Di Lullo G, Bises G: Metallothionein gene expression in the intestinal cell: modulation of mRNA and protein synthesis by copper and zinc. Biochem Soc Trans. 1991 Aug;19(3):283S.

1(0,0,0,1) Details