Metallothionein 1 activator

Another common biomarker for trace metal exposure is the metal-binding protein metallothionein, which regulates normal zinc and copper metabolism and provides a mechanism for metal detoxification. Changes in metallothionein activity provide a sensitive marker of trace metal exposure. 

Xu, C. (1993). cDNA cloning of a mouse factor that activates transcription from a metal response element of the mouse metallothionein-1 gene in yeast. DNA Cell Biol. 12, 517-525. 

Metallothioneins (MTs) are small proteins with an especial affinity for the binding of various heavy metals active in a wide range of reactions [95-97]. Besides their role in... 

Metallothioneins (MT) are unique 7-kDa proteins containing 20 cysteine molecules bounded to seven zinc atoms, which form two clusters with bridging or terminal cysteine thiolates. A main function of MT is to serve as a source for the distribution of zinc in cells, and this function is connected with the MT redox activity, which is responsible for the regulation of binding and release of zinc. It has been shown that the release of zinc is stimulated by MT oxidation in the reaction with glutathione disulfide or other biological disulfides [334]. MT redox properties led to a suggestion that MT may possesses antioxidant activity. The mechanism of MT antioxidant activity is of a special interest in connection with the possible antioxidant effects of zinc. (Zinc can be substituted in MT by some other metals such as copper or cadmium, but Ca MT and Cu MT exhibit manly prooxidant activity.)... 

Despite the conclusions in the cited literature about direct MT interaction with free radicals, the mechanism of MT antioxidant activity remains obscure. Markant and Pallauf [339] concluded that cysteine groups and not zinc are responsible for the inhibition of lipid peroxidation in hepatocytes. Maret and Vallee [340,341] also questioned the possibility of direct scavenging of free radicals by MT and suggested that zinc release is a major mechanism of antioxidant effects of metallothioneins. 

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

The effect of diet on vulnerability to lead makes interpretation of published information on experimental lead poisoning in waterfowl extremely difficult (Chasko et al. 1984). For example, many mallards on a diet of com die within 10 to 14 days after ingesting a single lead shot, whereas similar birds on a balanced commercial duck ration appear outwardly normal after ingesting as many as 32 pellets of the same size (Wobeser 1981). Also, multiple nutritional deficiencies may have additional effects in potentiating the toxicity of lead in mallards (Carlson and Nielsen 1985). Under conditions of reduced dietary calcium availability, such as can occur in acid-impacted environments, birds risk increased uptake of lead (and other metals) and may accumulate toxic concentrations more rapidly (Scheuhammer 1996). Enhanced accumulation of lead was accompanied by an increased synthesis of metallothioneins and a greater inhibition of ALAD activity (Scheuhammer 1996). 

Cows and calves fed low-zinc diets of 25 mg Zn/kg ration showed a decrease in plasma zinc from 1.02 mg/L at start to 0.66 mg/L at day 90 cows fed 65 mg Zn/kg diet had a significantly elevated (1.5 mg Zn/L) plasma zinc level and increased blood urea and plasma proteins (Ram-achandra and Prasad 1989). Biomarkers used to identify zinc deficiency in bovines include zinc concentrations in plasma, unsaturated zinc-binding capacity, ratio of copper to zinc in plasma, and zinc concentrations in other blood factors indirect biomarkers include enzyme activities, red cell uptake, and metallothionein content in plasma and liver (Binnerts 1989). 

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. 

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. 

Imbra RJ. Karin M (1987) Metallothionein gene eiqjression is regulated by serum factors and activators of protein kinase C. Mol Cell Biol 7 1358-1363... 

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