Metallothionein cadmium metabolism

In mammals, as in yeast, several different metallothionein isoforms are known, each with a particular tissue distribution (Vasak and Hasler, 2000). Their synthesis is regulated at the level of transcription not only by copper (as well as the other divalent metal ions cadmium, mercury and zinc) but also by hormones, notably steroid hormones, that affect cellular differentiation. Intracellular copper accumulates in metallothionein in copper overload diseases, such as Wilson s disease, forming two distinct molecular forms one with 12 Cu(I) equivalents bound, in which all 20 thiolate ligands of the protein participate in metal binding the other with eight Cu(I)/ metallothionein a molecules, with between 12-14 cysteines involved in Cu(I) coordination (Pountney et ah, 1994). Although the role of specific metallothionein isoforms in zinc homeostasis and apoptosis is established, its primary function in copper metabolism remains enigmatic (Vasak and Hasler, 2000). 

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. 

We have seen (Section 56.1.13.2.2) that cadmium can induce the synthesis of a Cd-binding protein in fact, the administration of copper, zinc, cadmium or mercury to animals induces the synthesis of these proteins called metallothioneins, which play an important role in the metabolism of these elements. 

Liu JX, Nordberg GF. 1995. Nephrotoxicities of aluminum and/or cadmium-metallothionein in rats Creatinine excretion and metabolism of selected essential metals. Pharmacol Toxicol 77 155-160. 

The metabolism of zinc is influenced by hormones, stress situations, lipopolysaccharides, toxins, oxygen radicals, lipid peroxidations, etc. This may lead to fluctuations in the zinc concentration, mainly due to the induction of metallothioneine (MT), which is a transport and intracellular depot protein. One third of this protein consists of cysteine, which binds zinc, copper, cadmium, cobalt and mercury. This protects the body from toxic heavy metal... 

Metallothioneins are a unique and widely distributed group of proteins. They are characterized by their low molecular weight (—6000), high cysteinyl content, and the ability to bind substantial numbers of metal ions (43). The proteins bind copper and zinc, thereby providing a mobile pool as part of the normal metabolism of these elements, and offer protection from the invasion of inorganic forms of the toxic elements cadmium, lead, and mercury. In addition, other metals, such as iron and cobalt, can be induced to bind. XAS is ideally suited to probe the environment of these different metal atoms (see Fig. 1), and the structural interpretations obtained from an analysis of the EXAFS data obtained in several such studies are summarized in Table 1(44). Thus, in each case, the data are consistent with the primary coordination of the metal deriving from the cysteinyl residues. 

The most definitive assessment of the metal composition of metalloproteins comes from the application of element-specific detection methods. CE-ICP-MS provides information not only about the type and quantity of individual metals bound to the proteins but also about the isotopes of each element as well [11,12]. Elemental speciation has become increasingly important to the areas of toxicology and environmental chemistry. Such analytical capability also opens up important possibilities for trace element metabolism studies. Figure 1 depicts the separation of rabbit liver metallothionein containing zinc, copper, and cadmium (the predominant metal) using CE-ICP-MS with a high-sensitivity, direct injection nebulizer (DIN) interface. UV detection (200 nm) was used to monitor the efficiency of the CE separation of the protein isoforms (MT-1 and MT-2), whereas ICP-MS detection made it possible to detect and quantify specific zinc, copper (not shown), and cadmium isotopes associated with the individual isoform peaks. 

Cadmium shares chemical properties with zinc and mercury, but in contrast to mercury, it is incapable of environmental methylation, due to the instability of the monoalkyl derivate. Similarities and differences also exist in the metabolism of Zn, Cd, and Hg. Metallothioneins and other Cd-binding proteins hold or transport Cd, Zn, and Hg within the body. Metallothioneins are metal-binding proteins of relatively low molecular mass with a high content of cysteine residues that have a particular affinity for cadmium, as well as for zinc and copper, and can affect its toxicity. 

Interaction with metallothionein is the basis for metabolic interactions between these metals. Metallothionein III is found in the human brain and differs from I and II by having six glutamic acid residues near the terminal part of the protein. Metallothionein III is thought to be a growth inhibitory factor, and its expression is not controlled by metals however, it does bind zinc. Another proposed role for metallothionein III is participation in the utilization of zinc as a neuromodulator, since metallothionein III is present in the neurons that store zinc in their terminal vesicles. Metallothionein IV occurs during differentiation of stratified squamous epithelium, but it is known to have a role in the absorption or toxicity of cadmium. 

George, S.G. and P. Young. The time course of effects of cadmium and 3-methylcholanthrene on activities of enzymes of xenobiotic metabolism and metallothionein levels in the plaice, Pleuronectes platessa. Comp. Biochem. Physiol. 83C 37—44, 1986. 

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. 

A number of zinc proteins have been described, the functions of which have not yet been fully identified. Of particular interest are the metallothioneins these are sulfur-rich proteins of low molecular weight and are rich in cadmium, zinc, and possibly other bivalent metals. It is suggested that the metallothioneins play a role in metal metabolism and detoxification (Kagi and Nordberg 1979, Foulker 1982, Hamer 1986). 

Even though MTs exist naturally with zinc and/or copper bound to them, the discovery of the first MT in 1957 from horse kidney was the result of a search for a cadmium protein. Since then, MTs have continuously challenged the interest of chemists and life scientists. A search in the SciFinder database with metallothionein as the entry yields about 15,000 publications and reveals more than 700 articles per year over the 1991-2001 decade. It also shows that developments in MT research have been covered by about 300 reviews. The widespread occurrence of MTs in nature suggests that they serve an important biological function not yet completely established. It would appear that MTs have no enzymatic activity, nor do they perform any catalytic role in known metabolic processes. Precise identification of the function of MTs accounts for the outstanding number of works available (as indicated by the search results) and prompts most of the research currently being undertaken. 

The difference in metal metabolism between sucklings and adults could also be attributed to differences in metal binding ligands. Me-tallothioneins were found to be higher in the newborn than in older rats (Bakka and Webb, 1981 Asokan and Tandon, 1981 Bell, 1980). However, it was also found that metallothioneins do not play a major role in tissue distribution and retention of cadmium (Wong and Klaassen, 1980 Johnson and Foulkes, 1980). Results obtained by Kello et al. (1979) with rats also suggest that metallothioneins in intestinal mucosa do not serve as determinants of cadmium absorption. 

Asokan P, Tandon SK (1981) Effect of cadmium on hepatic metallothionein level in early development of the rat. Environ. Res 24 201-206 Bakka A, Webb M (1981) Metabolism of zinc and copper in the neonate changes in concentrations and contents of thionein-bound Zn and Cu with age in the livers of the newborn of various mammalian species. Biochem. Pharmacol 30 721-725 Bell JU (1980) Induction of hepatic metallothionein in the immature rat following administration of cadmium. Toxicol. Appl Pharmacol 54 148-155 Barltrop D, Khoo HE (1979) The influence of dietary minerals and fat on the absorption of lead. The Sci. Total Environ 6 265-273 Bushnell PJ, DeLuca HF (1981) Lactose facilitates the intestinal absorption of lead in weanling rats. Science 211 61-63... 

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... 

Koropatnick J, Leibbrandt M, Cherian MG (1989) Organ-specific metallothionein induction in mice by x-irradiation. Radiat Res 119 356-365 Lehman-McKeeman LD, Kershaw WC, Klaassen CD (1991) Species differences in metallothionein regulation a comparison of the induction of isometallothioneins in rats and mice. In Klaassen CD, Suzuki KT (eds) Metallothionein in biology and medicine, CRC, Boca Raton, pp 121-132 Lui EMK (1987) Metabolism of copper and zinc in the liver and bone of perinatal guinea pig. Comp Biochem Physiol 86 173-183 Maitani T, Cuppage FE, Klaassen CD (1988) Nephrotoxicity of intravenously injected cadmium-metallothionein critical concentration and tolerance. Fund Appl Toxicol 10 98-108... 

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