Metallothionein, synthesis

Robbins, A.H. and Stout, C.D. (1992) Metallothioneins Synthesis, Structure and Properhes of Metallothioneins, Phytochelatins, and Metal-Thiolate Complexes (eds M.l. ShDman, C.F. Shawlll and KT. Suzuki), VCH Publishers, Weinheim, pp. 31—54. 

Mechanisms implicated in copper poisoning include free radical production, alteration in activities of several enzymes, and interference with metallothionein synthesis. At the cellular level,... 

Cadmium (soft, Cd2+) Renal toxicity Blocks sulfhydryl groups in enzymes and competes with zinc. Stimulates metallothionein synthesis and interferes with Cu(II) and Zn(II) metabolism. 

As stated previously, the total normal cytoplasmic free copper concentration is less than 10 18 M or less than one copper ion per cell. In thermodynamic terms, almost all hydrated copper ions are immediately and tightly coordinated by amino acids or biopolymers—peptides, proteins, and other species with free sulfur ligands. An excess of copper ions activates metallothionein synthesis for storage or removal of the excess. Copper chaperones mediate transfer of copper ions from extracellular or storage locations to their target proteins. Instability of copper ion concentrations in vivo results in various disease states. Three of these—FALS, Menkes, and Wilson s diseases—are described below. 

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. 

Stillman MJ, Shaw CF III, Suzuki KT (1992) Metallothioneins. Synthesis, structure, and properties of metallothioneins, phytochelatins and metal-thiolate complexes. VCH Publishers, New York Stratford IJ, Hoe S, Adams GE, Hardy C, Williamson C (1983) Abnormal radiosensitizing and cytotoxic properties of ortho-substituted nitroimidazoles. Int J Radiat Biol 43 31-43 Stubbe J, Kozarich JW (1987) Mechanisms of bleomycin-induced DNA degradation. Chem Rev 87 1107-1136... 

M. J. Stillman, C. F. Shaw 111, and K. T. Suzuki, eds, Metallothioneins Synthesis, Structure and Properties of Metallothioneins, Phytochelatins and Metalthiolate Ccomplexes , Wiley, New York, 1992. 

Both Szymanska and coworkersand Naganuma and coworkers found that bismuth is a potent inducer for accelerating metallothionein synthesis especially in the kidney. 

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. 

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 Elealth Perspect 1994 102 (suppi 3) 191-194. 

A striking feature of the cellular effects of bismuth compounds in animals (and one shared only by lead) is the production of intranuclear inclusion bodies of up to 5 ixm in diameter (87), for example, in the tubular epithelial cells of the kidney. Electron probe microanalysis shows that these contain both Bi and S, and so could be a complex with a Cys-rich protein such as metallothionein. Bismuth is known to be a potent inducer of renal metallothionein synthesis, and pretreatment of animals with bismuth salts can prevent some of the toxic side effects induced by cisplatin (88). The role of metallothionein in the pharmacology of bismuth remains to be established, but the strong involvement of zinc, also an inducer of metallothionein synthesis, in the metabolism of skin cells, for example, may be related. Like several other elements of Group V, the development of the biological chemistiy of Bi is hampered by the lack of good physical properties, in particular of a well-behaved NMR isotope. 

In contrast to inorganic mercury, alkyl mercuries do not induce metallothionein synthesis in renal or liver cells. 

As parent metal alters sodium balance and lipid metabolism it induces metallothionein synthesis. Nickel chloride affects the T-cell system and suppresses the activity of natural killer cells. If given orally or by inhalation, nickel chloride has been reported to decrease iodine uptake by the thyroid gland. 

Regulation of Gene Expression and Intracellular Copper Handling. Copper-dependent proteins act as transcription factors for specific genes, such as those regulating SOD and catalase. Metallothionein synthesis is controlled by copper-responsive transcription factors, and this protein is important in regulating the intracellular distribution of copper, Additional specialized proteins act as copper chaperones to deUver copper to intracellular sites and prevent oxidative damage by free copper ions. ... 

Goering PL. 1989. Acute exposure to formaldehyde induces hepatic metallothionein synthesis in mice. Toxicol Appl Phannacol 98 325-337. 

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. 

Morcillo MA, Rucandio MI and SantamarIa J (2000) Effect of gamma irradiation on liver metallothionein synthesis and lipid peroxidation in rats. Cell Mol Biol 46 435-444. 

Naganuma a, Satoh M and Imura N (1987) Prevention of lethal and renal toxicity of cis-diamine-dichloroplatinum(II) by induction of metallothionein synthesis without compromising its antitumour activity in mice. Cancer Res 47 983-987. 

Lehman, L.D., Poisner, A.M., 1984. Induction of metallothionein synthesis in cultured human trophoblasts by cadmium and zinc. J. Toxicol. Environ. Health 14, 419-432. 

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