Cadmium Mammalian metallothioneins

Metallothionein proteins are the most abundant intracellular, metal-binding proteins (Andrews, 2000). Four metallothionein isoforms have been identified in the mouse (MT-I-MT-IV) and are clustered within 50 kilobases of each other. In humans, there is one MTII gene and a cluster of MT I genes on chromosome 16 (Searl et al., 1984 West et al., 1990 Heuchel et al., 1995). The mammalian metallothioneins generally consist of 61 amino acids and 20 of these are cysteines (Heuchel et al., 1995). These cysteines are important for the binding of such bivalent metal ions, such as zinc, copper and cadmium. 

Figure 7 The (a) and a (b) cadmium-thiolate domain structures in mammalian metallothionein. Yellow spheres represent Cys-sulfurs and Green spheres represent Cd(ll) atoms. Based on models developed in our laboratory, for example, Ref. 41...

Metallothionein was first discovered in 1957 as a cadmium-binding cysteine-rich protein (481). Since then the metallothionein proteins (MTs) have become a superfamily characterized as low molecular weight (6-7 kDa) and cysteine rich (20 residues) polypeptides. Mammalian MTs can be divided into three subgroups, MT-I, MT-II, and MT-III (482, 483, 491). The biological functions of MTs include the sequestration and dispersal of metal ions, primarily in zinc and copper homeostasis, and regulation of the biosynthesis and activity of zinc metalloproteins. 

The two clusters differ in their metal-binding properties. Mammalian Cd, Zn metallothionein contains four Cd ions in cluster A and two Cd ions and one Zn ion in cluster B. 1157,1159 Calf liver metallothionein contains three Cu ions in cluster B with Cd-displaceable zinc ions in cluster A.1160 Studies on the binding of zinc and cadmium to human liver metallothionein show that binding occurs first in cooperative fashion to cluster A, followed by cooperative binding to cluster B. Incubation of the 7Cd metallothionein resulted in loss of Cd ions from cluster B initially.1161... 

The over-refined food of highly industrialized countries seems to produce zinc deficiency in the elderly, characterized by loss of acuity in taste and slow healing of cuts and abrasions. The mammalian kidney has a protein, metallothionein, which binds excess of zinc, cadmium, or mercury (Rupp, Voelter and Weser, 1974). 

In mammalian cells, some proteins combine with specific metals which are called metal proteins. For instance, transferrin is an iron carrier, ferritin can store iron [9], metallothionein (MT) can hold divalent metals such as zinc, copper, cadmium and so on [10, 11]. In chromosomes, there are some regions where metal proteins combine and regulate gene expressions. Zinc-finger motif proteins are famous for regulating transcriptimi and translation [12]. These metal-related... 

There are two isomers of metallothionein in mammalian cells MT-1 and MT-2. There are several metallothionein genes. The transcription of each is controlled by several heavy-metal response elements or by hormone response elements [14,15]. The mechanism of control of the metallothionein genes by its promoters is a subject of intense investigation. Despite all the knowledge gained so far, the function of the metallothionein is still uncertain. However, it appears that the metallothionein may play key roles in the homeostasis of zinc within cells and in the detoxification of excess copper or toxic nonessential metals like cadmium and mercury. 

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... 

Feldman AL, Failla ML, Cousins RJ (1978) Degradation of rat liver metallothioneins in vitro. Biochim Biophys Acta 544 638-646 Ferm VH, Carpenter SJ (1968) The relationship of cadmium and zinc in experimental mammalian teratogenesis. Lab Invest 18 429-432 Frery N, Nessman C, Girard F, Lafond J, Moreau T, Blot P, Lellouch J, Huel G (1993) Environmental exposure to cadmium and human birthweight. Toxicology 79 109-118... 

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). 

Metallothioneins (MTs) are small (6000-7000 Da), intracellular, cysteine-rich ( 33% of the amino acids are cysteines) metal binding proteins that were first discovered in 1957 in equine kidney cortex. The subsequent purification of this protein identified it as the only known native cadmium-containing protein. Further studies showed this protein to bind both essential (e.g., Cu and Zn) and nonessential (e.g., Cd and Hg) metal ions and to be truly ubiquitously distributed in nature [215-218]. Additionally, MT biosynthesis is induced at the transcriptional level by a wide range of factors, which includes heavy metal ions that were subsequently found bound to the protein. All of the above factors suggest a role for this protein in heavy metal homeostasis, transport and detoxification [215-218]. Despite 55 years of extensive studies on MTs, which has included the high resolution characterization of the 3D stmcture and metal binding properties [134,136,138,151,154,218-222], the essential physiological functional role(s) of MT remains elusive. Of particular note in these studies was the determination of the NMR solution structure of a mammalian MT in a tour deforce effort by the Wiithrich lab which resulted in the reinterpretation and correction of the mily mammalian MT crystal structure currently available [223,224]. 

The induction of DNA strand breaks and chromosomal aberrations by cadmium in mammalian cells was suppressed by antioxidants and antioxidant enzymes, indicating the involvement of ROS [34—36], Since the extent of ROS and damage to cellular macromolecules depends on the equilibrium between their generation and detoxification or repair, respectively, the occurrence of oxidative DNA damage is assumed to be due to an inhibition of the antioxidant defense by cadmium, such as the antioxidant enzymes catalase, superoxide dismutase, glutathione reductase, and glutathione peroxidase. One other mechanism proposed consists in the displacements of redox active metal ions, e.g., Fe ", for example in metallothionein, giving rise to Fenton reactions [35-37]. 

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