Cadmium induced metallothionein

Its synthesis in organisms is induced by the above-mentioned metals and is involved in the storage of these metals in organs. Zinc metallothionein can detoxify free radicals. Cadmium-induced metallothionein is able to bind cadmium intracel-lularly and in this way protects the organism against the toxicity of this metal. Cadmium is transported in the plasma as a complex with metallothionein and may be toxic to the kidney when excreted in the glomerular filtrate. 

Munoz, A., Laib, F., Petering, D.H. and Shaw, C.F. Ill (1999) Characterization of the cadmium complex of peptide 49-61 a putative nudeation center for cadmium-induced folding in rabbit liver metallothionein IIA. Journal of Biological Inorganic Chemistry, 4, 495—507. 

The binding of transcription factors to nucleotide sequences, which facilitates gene transcription, can be influenced by chemicals. For example, cadmium binds to a metal-binding protein factor, MFF-1, in place of zinc and so induces metallothionein synthesis. This, as it happens is a detoxication, as metallothionein binds cadmium. 

High levels of zinc stimulate the synthesis of metallothionein in the small intestines. The elevated levels of metallothionein then serve as a depot for the binding of high levels of zinc consumed in subsequent meals. The induced protein has been shown to limit the amount of zinc entering the bloodstream with consumption of a high-zinc diet (Menard ef o/., 1981). High doses of copper can induce metallothionein synthesis to the same extent as can zinc. At levels near those found in the diet, zinc is a potent inducer while copper is only a weak inducer. Normally, hepatic metaiiothionein contains mainly zinc, whereas kidney metallothionein contains copper and, when present in the diet, cadmium. The copper entering the liver may be stored in hepatic metallothionein and released into the plasma in ceruloplasmin or secreted in the bile later. 

Some causal relations among various urinary indices were identified using path analysis method. Cadmium-induced renal dysfunction develops in the following order Cd exposure —> increased p2-microglobulin and/or metallothionein —> increased excretion of amino-nitrogen and/or total protein —> increased excretion of glucose [76]. 

In Chinese Cd-exposed workers it was demonstrated that those with a high ability to induce metallothionein suffered less tubular damage than those with a low ability to induce metallothionein in peripheral blood lymphocytes [159]. Similar observations were reported from a population group in China environmentally exposed to cadmium [160]. These observations give support for an important role of metallothionein induction in humans and that such induction in peripheral blood lymphocytes can be used as a biomarker of individual sensitivity to development of renal damage. 

Chen L, JinT, Huang B, Chang X, Lei L, Nordberg GF, Nordberg M. Plasma metallothionein antibody and cadmium-induced renal dysfunction in an occupational population in China.Toxicol Sci 2006 91 104-112. 

Olsson, P.-E., A. Larsson and C. Haux. Influence of seasonal changes in water temperature on cadmium inducibility of hepatic and renal metallothionein in rainbow trout. Mar. Environ. Res. 42 41-44, 1996. 

Copper is a cofactor in several enzymes, including lysyl oxidase and superoxide dismutase. Ceruloplasmin, a deep-blue glycoprotein, is the principal copper-containing protein in blood. It is used to transport Cu2+ and maintain appropriate levels of Cu2+ in the body s tissues. Ceruloplasmin also catalyzes the oxidation of Fe2+ to Fe3+, an important reaction in iron metabolism. Because the metal is widely found in foods, copper deficiency is rare in humans. Deficiency symptoms include anemia, leukopenia (reduction in blood levels of white blood cells), bone defects, and weakened arterial walls. The body is partially protected from exposure to excessive copper (and several other metals) by metal-lothionein, a small, metal-binding protein that possesses a large proportion of cysteine residues. Certain metals (most notably zinc and cadmium) induce the synthesis of metallothionein in the intestine and liver. 

Ishido M, Tohyama C, Suzuki T. Cadmium-bound metallothionein induces apoptosis in rat kidneys, but not in cultured kidney LLC-PK1 cells. Life Sci 1999 64 797-804. 

Nordberg GF, Jin T, Nordberg M. Subcellular targets of cadmium nephrotoxicity cadmium binding to renal membrane proteins in animals with or without protective metallothionein synthesis. Environ Flealth Perspect 1994 102(suppl 3) 191-194. Fowler BA, Akkerman M. The role of Ca + + In cadmium-induced renal tubular cell Injury.. In Cadmium in the human environment toxicity and carcinogenicity. Nordberg G, Herber R, Alessio L (editors). International Agency for Research on Cancer (lARC) Scientific Publications vol 118, Lyon 1992 p. 271-277. 

As with the mutagenic and carcinogenic action of metals, the teratogenic effects can be modified by additional influences. For example, the teratogenicity of cadmium in mice was decreased by bismuth-induced metallothionein (Naruse and Hayashi... 

Experimental studies have shown that cadmium can induce metallothionein synthesis in the placenta, particularly in trophoblasts. Metallothionein in the placenta binds the essential trace metals, zinc and copper. The mechanism whereby essential metals are preferentially transported to the fetus and cadmium retained is not known. Experimental studies have shown that exposure of pregnant animals to high levels of cadmium early in pregnancy is teratogenic. Human studies suggest maternal cadmium exposure may reduce fetal birth weight and that this may be an indirect effect of zinc deprivation that occurs with cadmium exposure. 

Goyer RA, Cherian MG, Delaquerriere-Richardson L (1984) Correlation of parameters of cadmium exposure with onset of cadmium-induced nephropathy in rat. J Environ Pathol Toxicol Oncol 5 89-100 Goyer RA, Haust MD, Cherian MG (1992) Cellular localization of metallothionein in human term placenta. Placenta 13 349-355 Gulson B, Mahaffey KR (1993) Contribution of tissue lead to blood lead of adult female subjects bases on stable lead isotope methods (unpublished)... 

De SK, McMaster MT, Dey SK, Andrews GK (1989) Cell-specific metallothionein gene expression mouse decidua and placentae. Development 107 611-621 De SK, Enders GC, Andrews GK (1991) High levels of metallothionein mRNAs in male germ cells of the adult mouse. Mol Endocrinol 5 628-636 Dorian C, Gattone II VH, Klaassen CD (1992) Renal cadmium deposition and injury as a result of accumulation of cadmium-metallothionein (Cd-MT) by the proximal convoluter tubules. Toxicol Appl Pharmacol 114 173-181 Dudley RE, Gammal LM, Klaassen CD (1985) Cadmium-induced hepatic and renal injury in chronically exposed rats likely role of hepatic cadmium-metallothionein in nephrotoxicity. Toxicol Appl Pharmacol 77 414-426 Ershoff BH (1948) Conditioning factors in nutritional disease. Physiol Rev 28 107-137... 

Gallant KR, Cherian MG (1987) Changes in dietary zinc result in specific alterations of metallothionein concentrations in newborn rat liver. J Nutr 117 706-716 Gallant KR, Cherian MG (1989) Metabolic changes in glutathione and metallothionein in newborn rat liver. J Pharmacol Exp Ther 249 631-637 Goering PL, Klaassen CD (1984a) Tolerance to cadmium-induced toxicity depends on presynthesized metallothionein in liver. J Toxicol Environ Health 14 803-812... 

Coogan TP, Bare RM, Waalkes MP (1992) Cadmium-induced DNA damage effects of zinc pretreatment. Toxicol Appl Pharmacol 113 227-233 Coogan TP, Bare RM, Bjornson EJ, Waalkes MP (1994) Enhanced metallothionein gene expression protects against cadmium genotoxicity in cultured rat liver cells. J Toxicol Environ Health (in press)... 

Imura N, Satoh M, Naganuma A (1991) Possible application of metallothionein in cancer therapy. In Klaassen CD, Suzuki KT (eds) Metallothionein in biology and medicine. CRC Press, Boca Raton, pp 375-382 Ito T, Sawauchi K (1966) Inhibitory effects on cadmium-induced testicular damage by pretreatment with smaller cadmium doses. Okajimas Folia Anat Jpn 42 107-117... 

Studies on mutagenesis by metal compounds may be complicated by inducible tolerance mechanisms in some cells. Metallothioneins (MT) are small cysteine-rich proteins which bind a number of metals with high affinity. The reader is referred to Chap. 5 in this volume for more detail. Besides cadmium, zinc, and copper salts, a number of other metal salts have also been shown to induce MT synthesis and/or to bind to the MT protein. Hg(II), Co(II), and Ni(II), but not Pb(II), induce MT synthesis in primary cultures of rat hepatocytes (Bracken and Klaassen 1987), and may do so in the cultured cells used for mammalian mutagenesis experiments. Thus, under some experimental protocols, the metal salt being assayed may itself induce metallothionein, or the results of mutagenicity assays may be confounded by components of the medium or serum which affect the levels of metallothionein in the cell (Rossman and Goncharova, unpublished). 

Cd(II) can bind to both the bases and the phosphate groups of DNA, and tends to destabilize the DNA helix (Jacobson and Turner 1980). However, these effects do not constitute DNA damage in the usual sense of the term (i.e., strand breaks, cross-links, adducts). Incubation of DNA with Cd(II) alone or with H2O2 did not result in strand breaks (Roy and Rossman, unpublished data). Cadmium-metallothionein complex is able to induce DNA strand breaks (Muller et al. 1991). However, the production of DNA strand breaks in cells by a cadmium-metallothionein complex is unlikely. Pretreatment of cells with Zn(II) to induce metallothionein resulted in decreased toxicity and DNA strand breaks by Cd(II) (Coogan et al. 1992). Transfection of a metallothionein overproducing plasmid into G12 cells abolished the mutagenicity of Cd(II) (Goncharova and Rossman, in preparation). 

Mecfianisni of toxicologic damage. Cadmium induces the formation of metallothionein and binds to it in the tissues. The cadmium-metallothionein complex promotes renal accumulation. Metabolism releases free cadmium, which is nephrotoxic. 

There are sensitive methods available for the quantification of tubular proteinuria in populations exposed to cadmium occupationally or environmentally. RBP, p2-M, al-microglobuhn (al-M, also called protein HC), metallothionein, and enzymes such as N-acetyl- p-D-glucosaminidase (NAG) in human urine are used as biomarkers of cadmium-induced effects [56-61]. However, the effects are not specific to cadmium exposure, but may also occur due to various renal diseases or nephrotoxic agents other than cadmium. 

Cadmium is nutritionally non-essential, toxic and a ubiquitous environmental pollutant. It is found in leafy vegetables, grains and cereals, and since it is present in substantial amounts in tobacco leaves, cigarette smokers on a packet a day can easily double their cadmium intake. It has a long biological half-life (17-30 years in man), accumulates in liver and kidneys and its toxicity involves principally kidney and bone (Goyer, 1997).While Cd interferes primarily with calcium, it also interacts with zinc and can induce the synthesis of metallothionein. Cadmium bound to metallothionein in liver or kidney is thought to be non-toxic, but cadmium in plasma... 

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