Metallothionein — Aspects related to copper and zinc metabolism

  • R. J. Cousins


Metallothionein is a cysteine-rich, low molecular weight protein that binds zinc, copper and cadmium. It is inducible in liver, kidney and intestine by glucocorticoids, changes in the dietary zinc supply, acute administration of various metals, food restriction, infection, stress and endotoxin treatment. Regulation of synthesis involves altered gene expression. The protein is fairly rapidly degraded when zinc is the primary metal species bound, but the degradation rate is diminished when cadmium or copper are bound as well. The net result of metallothionein production seems to be accumulation of bound metal and/or intracellular metal redistribution. The accumulation of copper in various tissues of individuals with Menkes' and Wilson's diseases may be related to altered metallothionein turnover. The physiological function is not clear, but the response of metallothionein to hormonal stimuli is suggestive of an important role in cellular metabolism.


Zinc Cadmium Glucocorticoid Food Restriction Metal Species 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Anderson, R. D. and Weser, U. Partial characterization and translation in vitro of rat liver metallothionein messenger ribonucleic acid.Biochem. J. 175 (1978) 841–852PubMedGoogle Scholar
  2. Bell, J. V. and Waalkes, M. P. Role of hepatic metallothionein during perinatal development in the rat. In Foulkes, E. C. (ed.)Biological Roles of Metallothionein, Elsevier/North-Holland, New York, 1982Google Scholar
  3. Beratis, N. G., Rice, P., LaBadie, G. and Hirschhorn, J.64Cu metabolism in Menkes and normal cultured skin fibroblasts.Pediatr. Res. 12 (1978) 699–702PubMedGoogle Scholar
  4. Brady, F. O. The physiological function of metallothionein.Trends Biochem. Sci. 7 (1982) 143–145Google Scholar
  5. Brady, F. O., Webb, M. and Mason, R. Zinc and copper metabolism in neonates: role of metallothionein in growth and development in the rat. In Foulkes, E. C. (ed.)Biological Roles of Metallothionein, Elsevier/North-Holland, New York, 1982Google Scholar
  6. Bremner, I. and Davies, N. T. The induction of metallothionein in rat liver by zinc injection and restriction of food intake.Biochem. J. 149 (1975) 733–738PubMedGoogle Scholar
  7. Bremner, I. and Davies, N. T. Studies on the appearance of a hepatic copper-binding protein in normal and zinc-deficient rats.Br. J. Nutr. 36 (1976) 101–112PubMedGoogle Scholar
  8. Bremner, I., Hoekstra, W. G., Davies, N. T. and Young, B. W. Effect of zinc status of rats on the synthesis and degradation of copper-induced metallothioneins.Biochem. J. 174 (1978) 883–892PubMedGoogle Scholar
  9. Bremner, I. and Young, B. W. Isolation of (copper, zinc)-thioneins from the liver of copper-injected rats.Biochem. J. 157 (1976a) 517–520PubMedGoogle Scholar
  10. Bremner, I. and Young, B. W. Isolation of (copper, zinc)-thioneins from pig liver,Biochem. J. 155 (1976b) 631–635PubMedGoogle Scholar
  11. Buhler, R. H. O. and Kagi, J. H. R. Human hepatic metallothioneins.FEBS Lett. 39 (1974) 229–234PubMedGoogle Scholar
  12. Chan, W. Y., Granica, A. D. and Rennert O. M. Inducibility of metallothionein biosynthesis in cultured normal and Menkes kinky hair disease fibroblasts: Effects of copper and cadmium.Pediatr. Res. 13 (1979) 197–203PubMedGoogle Scholar
  13. Chang, J. C., and Kan, Y. W. A sensitive new prenatal test for sickle-cell anemia.N. Engl. J. Med. 307 (1982) 30–32PubMedGoogle Scholar
  14. Cousins, R. J. Relationship of metallothionein synthesis and degradation to intracellular zinc metabolism. In Foulkes, E. C. (ed.)Biological Roles of Metallothionein, Elsevier/North Holland, New York, 1982Google Scholar
  15. Cousins, R. J. and Weiner, A. L. Hormonal regulation of copper and zinc metabolism in isolated rat liver parenchymal cells. In Sorenson, J. R. J. (ed.)Inflammatory Diseases and Copper, Humana, Clifton, NJ, 1982Google Scholar
  16. Danielson, K. G., Ohi, S. and Huang, P. C. Immunochemical detection of metallothionein in specific epithelial cells of rat organs.Proc. Natl. Acad. Sci. USA 79 (1982) 2301–2304PubMedGoogle Scholar
  17. Danks, D. M., Campbell, P. E., Walker-Smith, J., Stevens, B. J., Gillespie, J. M. Blomfield, J. and Turner, B. Menkes kinkyhair syndrome.Lancet 1 (1972) 1100–1103PubMedGoogle Scholar
  18. Durnam, D. and Palmiter, R. Transcriptional regulation of the mouse metallothionein-I gene by heavy metals.J. Biol. Chem. 256 (1981) 5712–5716PubMedGoogle Scholar
  19. Etzel, K. R. and Cousins, R. J. Hormonal regulation of liver metallothionein zinc: Independent and synergistic action of glucagon and glycocorticoids.Proc. Soc. Exp. Biol. Med. 167 (1981) 233–236PubMedGoogle Scholar
  20. Etzel, K. R., Shapiro, S. G. and Cousins, R. J. Regulation of liver metallothionein and plasma zinc by the glucocorticoid dexamethasone.Biochem. Biophys. Res. Commun. 89 (1979) 1120–1126PubMedGoogle Scholar
  21. Etzel, K. R., Swerdel, M. R., Swerdel, J. N. and Cousins, R. J. Endotoxin induced changes in copper and zinc metabolism in the Syrian hamster.J. Nutr. 112 (1982) 2363–2373PubMedGoogle Scholar
  22. Failla, M. L. and Cousins, R. J. Zinc uptake by isolated rat liver parenchymal cells.Biochim. Biophys. Acta 538 (1978a) 435–444PubMedGoogle Scholar
  23. Failla, M. L. and Cousins, R. J. Zinc accumulation and metabolism in primary cultures of rat liver cells: Regulation by glucocorticoids.Biochim. Biophys. Acta 543 (1978b) 293–304.PubMedGoogle Scholar
  24. Failla, M. L., Cousins, R. J. and Mascenik, M. Cadmium accumulation and metabolism by rat liver parenchymal cells in primary monolayer culture.Biochim. Biophys. Acta 583 (1979) 63–72PubMedGoogle Scholar
  25. Feldman, S. L. and Cousins, R. J. Degradation of hepatic zinc-thionein following parenteral zinc administrations.Biochem. J. 160 (1976) 583–588PubMedGoogle Scholar
  26. Feldman, S. L., Failla, M. L. and Cousins, R. J. Degradation of liver metallothioneins in vitro.Biochim. Biophys. Acta 544 (1978b) 638–646PubMedGoogle Scholar
  27. Feldman, S. L., Squibb, K. S. and Cousins, R. J. Degradation of cadmium thionein in rat liver and kidney.J. Toxicol. Environ. Health 4 (1978a) 805–813PubMedGoogle Scholar
  28. Foulkes, E. C. (ed.)Biological Role of Metallothionein, Elsevier/North-Holland, New York 1982Google Scholar
  29. Garvey, J. S. and Chang, C. C. Detection of circulating metallothionein in rats injected with zinc or cadmium.Science 211 (1981) 805–807Google Scholar
  30. Garvey, J. S., Vander Mallie, R. J. and Chang, C. C. Radioimmunoassay of metallothioneins.Meth. Enzymol. 84 (1982) 121–138PubMedGoogle Scholar
  31. Glanville, N., Durnam, D. M. and Palmiter, R. D. Structure of mouse metallothionein-I gene and its mRNA.Nature (London) 292 (1981) 267–269PubMedGoogle Scholar
  32. Goka, T. J., Stevenson, R. E., Hefferan, P. M. and Howell, R. R. Menkes disease: A biochemical abnormality in cultured human fibroblasts.Proc. Natl. Acad. Sci. USA 73 (1976) 604–606PubMedGoogle Scholar
  33. Hager, L. J. and Palmiter, R. D. Transcriptional regulation of mouse liver and metallothionein-1 gene by glucocorticoids.Nature (London) 291 (1981) 340–342PubMedGoogle Scholar
  34. Hall, A. C., Young, B. W. and Bremner, I. Intestinal metallothionein and the mutual antagonism between copper and zinc in the rat.J. Inorg. Biochem. 11 (1979) 57–66PubMedGoogle Scholar
  35. Held, D. D. and Hoekstra, W. G.In vitro degradation of metallothionein by rat liver lysosomes.Fed. Proc. 38 (1979) 734 (2674 abstr.)Google Scholar
  36. Jackson, M. J., Jones, D. A. and Edwards, R. H. T. Zinc absorption in the rat.Br. J. Nutr. 46 (1981) 15–27PubMedGoogle Scholar
  37. Jacobs, A. and Worwood, M. Ferritin in serum.N. Engl. J. Med. 292 (1975) 951–954PubMedGoogle Scholar
  38. Kagi, J. H., Himmelhock, S. R., Whanger, P. D., Bethune, J. L. and Vallee, B. L. Equine hepatic and renal metallothioneins.J. Biol. Chem. 249 (1974) 3537–3542PubMedGoogle Scholar
  39. Kagi, J. H. and Nordberg, M.Metallothionein, Birkhauser Verlag, Basel, 1979Google Scholar
  40. Kagi, J. H. and Vallee, B. L. Metallothionein: a cadmium- and zinc-containing protein from equine renal cortex.J. Biol. Chem. 235 (1960) 3460–3465PubMedGoogle Scholar
  41. Karin, M. and Herschman, H. R. Dexamethasone stimulation of metallothionein synthesis in HeLa cell cultures.Science 204 (1979) 176–177PubMedGoogle Scholar
  42. Klaasen, C. D. and Wong, K. L. Mineral role of the high concentration of hepatic metallothionein in the newborn rat in the toxicity, distribution and excretion of cadmium. In Foulkes, E. C. (ed.)Biological Roles of Metallothionein, Elsevier/North-Holland, New York, 1982Google Scholar
  43. Kojima, Y., Berger, C., Vallee, B. L. and Kagi, J. H. R. Amino-acid sequence of equine renal metallothionein-1.Proc. Natl. Acad. Sci. USA 73 (1976) 3413–3417PubMedGoogle Scholar
  44. LaBadic, G. U., Hirschhora, K., Katz, S. and Beratis, N. G. Increased copper metallothionein in Menkes cultured skin fibroblasts.Pediatr. Res. 15 (1981) 257–261PubMedGoogle Scholar
  45. Li, T. Y., Kraker, A. J., Shaw, C. F. and Petering, D. H. Ligand substitution reactions of metallothioneins with EDTA and apo-carbonic anhydrase.Proc. Natl. Acad. Sci. USA 77 (1980) 6334–6338PubMedGoogle Scholar
  46. Lombeck, I., Schnippering, H. G., Ritzl, F., Feinendegen, L. E. and Bremer, H. J. Absorption of zinc in acrodermatitis enteropathica.Lancet 1 (1975) 855Google Scholar
  47. Madapallimatam, G. and Riordan, J. R. Antibodies to the low molecular weight copper binding protein from liver.Biochem. Biophys. Res. Commun. 77 (1977) 1286–1293PubMedGoogle Scholar
  48. Mayo, K. E. and Palmiter, R. D. Glucocorticoid regulation of the mouse metallothionein I gene is selectively lost following amplification of the gene.J. Biol. Chem. 257 (1982) 3061–3067PubMedGoogle Scholar
  49. McCormick, C., Menard, M. P. and Cousins, R. J. Induction of hepatic metallothionein by feeding zinc to rats of depleted zinc status.Am. J. Physiol. 240 (1981) E414-E421PubMedGoogle Scholar
  50. Menard, M. P., McCormick, C. C. and Cousins, R. J. Regulation of intestinal metallothionein biosynthesis in rats by dietary zinc.J. Nutr. 111 (1981) 1353–1361PubMedGoogle Scholar
  51. Mercer, J. F. B., Lazdins, I., Stevenson, T., Camakaris, J. and Danks, D. M. Copper induction of translatable metallothionein messenger RNA.Biosci. Rep. 1 (1981) 793–800PubMedGoogle Scholar
  52. Oh, S. H., Deagan, J. T., Whanger, P. D. and Wesung, P. H. Biological function of metallothionein. V. Its induction in rats by various stresses.Am. J. Physiol. 234 (1978) E282-E285PubMedGoogle Scholar
  53. Ohi, S., Cardenosa, G., Pine, R. and Huang, P. C. Cadmium-induced accumulation of metallothionein messenger RNA in rat liver.J. Biol. Chem. 256 (1981) 2180–2184PubMedGoogle Scholar
  54. Ohtake, H., Hasegaewa, K., and Koga, M. Zinc-binding protein in the liver of neonatal, normal and partially hepatectomized rats.Biochem. J. 174 (1978) 999–1005PubMedGoogle Scholar
  55. Olafson, R. W. Differential pulse polarographic determination of murine metallothionein induction kinetics.J. Biol. Chem. 256 (1981) 1263–1268PubMedGoogle Scholar
  56. Otvos, J. D. and Armitage, I. M. Structure of the metal clusters in rabbit liver metallothionein.Proc. Natl. Acad. Sci. USA 77 (1980) 7094–7098PubMedGoogle Scholar
  57. Ouellette, A. J. Metallothionein mRNA expression in fetal mouse organs.Devel. Biol. 92 (1982) 240–246Google Scholar
  58. Piscator, M. On cadmium in normal human kidneys together with a report on the isolation of metallothionein from livers of cadmium-exposed rabbits.Nord. Hyg. Tidskr. 45 (1964) 76–82PubMedGoogle Scholar
  59. Richards, M. P. and Cousins, R. J. Mammalian zinc homeostasis: Requirement for RNA and metallothionein synthesis.Biochem. Biophys. Res. Commun. 64 (1975) 1215–1223PubMedGoogle Scholar
  60. Richards, M. P. and Cousins, R. J. Zinc binding protein: Relationship to short-term changes in zinc metabolism.Proc. Soc. Exp. Biol. Med. 153 (1976) 52–56PubMedGoogle Scholar
  61. Riordan, J. R. and Jolicoeur-Paquet, L. Metallothionein accumulation may account for intracellular copper retention in Menkes' disease.J. Biol. Chem. 257 (1982) 4639–4645PubMedGoogle Scholar
  62. Ryden, L. and Deutsch, H. F. Preparation and properties of the major copper binding component in human fetal liver, its identification as metallothionein.J. Biol. Chem. 253 (1978) 519–524PubMedGoogle Scholar
  63. Shaikh, Z. A. and Lucis, O. J. Induction of cadmium binding protein.Fed. Proc. Fed. Am. Soc. Exp. Biol. 29 (1970) 298Google Scholar
  64. Shapiro, S. G. and Cousins, R. J. Induction of rat liver metallothionein mRNA and its distribution between free and membrane-bound polysomes.Biochem. J. 190 (1980) 755–764PubMedGoogle Scholar
  65. Shapiro, S. G., Squibb, K. S., Markowitz, L. A. and Cousins, R. J. Cell-free synthesis of metallothionein directed by rat liver polyadenylated messenger RNA.Biochem. J. 175 (1978) 833–840.PubMedGoogle Scholar
  66. Smith, K. T. and Cousins, R. J. Quantitative aspects of zinc-absorption by isolated vascularly perfused rat intestine.J. Nutr. 110 (1980) 316–323.PubMedGoogle Scholar
  67. Soboscinski, P., Canterbury, W. J., Mapes, C. A. and Dinterman, R. E. Involvement of hepatic metallothionein in hypozincemia associated with bacterial infection.Am. J. Physiol. 234 (1978) E399-E406.PubMedGoogle Scholar
  68. Squibb, K. S. and Cousins, R. J. Control of cadmium binding protein synthesis in rat liver.Environ. Physiol. Biochem. 4 (1974) 24–30.PubMedGoogle Scholar
  69. Squibb, K. S., Cousins, R. J. and Feldman, S. L. Control of zinc-thionein in rat liver.Biochem. J. 164 (1977) 223–228.PubMedGoogle Scholar
  70. Starcher, B. C., Glauber, J. G. and Madaras, J. R. Zinc absorption and its relationship to intestinal metallothionein.J. Nutr. 110 (1980) 1391–1397.PubMedGoogle Scholar
  71. Suzuki, K. T. Direct connection of high-speed liquid chromatograph (equipped with gel permeating column) to atomic absorption spectrophotometer for metalloprotein analysis: metallothionein.Anal. Biochem. 102 (1980) 31–34.PubMedGoogle Scholar
  72. Swerdel, M. R. and Cousins, R. J. Induction of kidney metallothionein and metallothionein messenger RNA by zinc and cadmium.J. Nutr. 112 (1982) 801–809PubMedGoogle Scholar
  73. Swerdel, M. R. and Cousins, R. J. (1983) unpublished resultsGoogle Scholar
  74. Udom, A. O. and Brady, F. O. Reactivation in vitro of zinc-requiring apoenzymes by rat liver zinc-thionein.Biochem. J. 187 (1980) 329–335PubMedGoogle Scholar
  75. Webb, M. Binding of cadmium ions by rat liver and kidney.Biochem. Pharmacol. 21 (1972) 2751–2765PubMedGoogle Scholar
  76. Webb, M. and Cain, K. Functions of metallothionein.Biochem. Pharmacol. 31 (1982) 137–142PubMedGoogle Scholar
  77. Weiner, A. L. and Cousins, R. J. Copper accumulation and metabolism in primary monolayer cultures of rat liver parenchymal cells.Biochim. Biophys. Acta 629 (1980) 113–125PubMedGoogle Scholar
  78. Weiner, A. L. and Cousins, R. J. Hormonally produced changes in caeruloplasmin synthesis and secretion in primary cultured rat hepatocytes.Biochem. J. 212 (1983) 297–304PubMedGoogle Scholar
  79. Whanger, P. D. and Ridlington, J. W. Role of metallothionein in zinc metabolism. In Foulkes, E. C. (ed.)Biological Roles of Metallothionein, Elsevier/North-Holland, New York, 1982Google Scholar
  80. Winge, D. R., Premakumar, R., Wiley, R. D. and Rajagopalan, K. V. Copper-chelatin: Purification and properties of a copper-binding protein from rat liver.Arch. Biochem. Biophys. 170 (1975) 253–266PubMedGoogle Scholar
  81. Zelazowski, A. J. and Piotrowski, J. K. A modified procedure for determination of metallothionein-like proteins in animal tissues.Acta Biochem. Pol. 24 (1977) 97–103Google Scholar

Copyright information

© SSIEM and MTP Press Limited 1983

Authors and Affiliations

  • R. J. Cousins
    • 1
  1. 1.Department of Food Science & Human NutritionUniversity of FloridaGainesvilleUSA

Personalised recommendations