Metallothionein oxidative stress

A battery of different biochemical quantitative assays was applied to many different tissues and species. DNA damage and lipid peroxidation assays measure the direct impact of genotoxics and oxidant pollutants [16,17] whereas alteration of GSH levels in liver is a marker for oxidative stress [18]. Mercury and other heavy metals are known to induce metallothionein levels in different tissues although this effect is variable in different species and organs [19-22]. 

Metallothionein content MT Stress protein Cd, Cu, Zn, Hg, oxidative stress Liver tissue 6-15... 

These proteins are important for binding potentially toxic metals such as cadmium, mercury, and lead, which all bind to sulfydryl groups. Consequently, the binding and removal of these metals are protective functions. Metallothioneins are markedly induced by cadmium exposure and the small protein, rich in SH groups, can then sequester the metal. They also may have a protective role in oxidative stress and protect redox-sensitive processes. The protein also has a role in cadmium nephrotoxicity (see chap. 7). 

Feng W, Benz FW, Cai J, Pierce WM, Kang YJ (2006) Metallothionein disulfides are present in metallothionein-overexpressing transgenic mouse heart and increase under conditions of oxidative stress. J Biol Chem 281 681-7... 

Thornalley PJ, Vasak M (1985) Possible role for metallothionein in protection against radiation-induced oxidative stress. Kinetics and mechanism of its reaction with superoxide and hydroxyl radicals. Biochim Biophys Acta 827 36-44... 

Andrews, G.K. (2000) Regulation of metallothionein gene expression by oxidative stress and metal ions. Biochem. Pharmacol., 59, 95-104. 

Dalton TP, Li Q, Bittel D, Liang L, Andrews GK (1996) Oxidative stress activates metal-responsive transcription factor-1 binding activity. Occupancy in vivo of metal response elements in the metallothionein-I gene promoter. J Biol Chem 271 26233-26241 Danscher G, Howell G, Perez-Clausell J, Hertel N (1985) The dithizone, Timm s sulphide silver and the selenium methods demonstrate a chelatable pool of zinc in CNS. A proton activation (PIXE) analysis of carbon tetrachloride extracts from rat brains and spinal cords intravitally treated with dithizone. Histochemistry 83 419 22 Danscher G, Jensen KB, Frederickson CJ, Kemp K, Andreasen A, Juhl S, Stoltenberg M, Ravid R (1997) Increased amount of zinc in the hippocampus and amygdala of Alzheimer s diseased brains a proton-induced X-ray emission spectroscopic analysis of cryostat sections from autopsy material. J Neurosci Methods 76 53-59... 

Mehta, A., Flora, S.J.S. (2001). Possible role of metal redistribution, hepatotoxicity and oxidative stress in chelating agents induced hepatic and renal metallothionein in rats. Food. Chem. Toxicol. 39 1029-38. 

Lazo, J., Kondo, Y, DeUapiazza, D., Michalska, A., Choo, K., and Pitt, B. R. (1995). Enhcmced sensitivity to oxidative stress in cultured embryonic cells from transgenic mice different in metallothionein I and II genes. /. Biol. Chem. 27,5506-5510. 

Nutritional status Many antioxidants are present in the diet (e.g., vitamin E, vitamin C, peptides for the synthesis of glutathione, trace metals, and minerals like zinc). However, poor nutrition or malabsorption leads to deficiency of these key vitamins and antioxidants. This may impair the antioxidative defense capacity, leading to drug-induced oxidative stress and lower threshold for DILL In a preclinical study, a mere 1.6- and 2.1-fold increase in liver zinc content was associated with an increase in liver metallothionein between 50- and 200-fold.38 Metallothionein is a key antioxidant protein in vivo capable of scavenging most common kinds of oxidative species.39 It is therefore conceivable that a lack of sufficient dietary available zinc could compromise a patient s hepatic metallothionein levels and his or her antioxidant reserve capabilities in liver. 

The data indicate that zinc-induced metallothionein binds mercury in the renal cortex and shifts the distribution of mercury from its site of toxicity at the epithelial cells of the proximal tubules. Thus, the renal content of mercury is increased, yet less is available to cause toxicity. In contrast, the renal toxicity of mercuric chloride is exacerbated in zinc-deficient animals (Fukino et al. 1992). In the zinc-deficient state, less mercury accumulates in the kidneys, but the toxicity is greater. The mechanism of the protection appears to involve more than simply a redistribution of renal mercury, because in the absence of mercury exposure, zinc deficiency increases renal oxidative stress (increased lipid peroxidation, decreased reduced ascorbate). When mercury exposure occurs, the oxidative stress is compounded (increased lipid peroxidation and decreased glutathione and glutathione peroxidase). Thus, zinc appears to affect the biochemical protective mechanisms in the kidneys as well. 

The co-administration of M. oleifera seed powder with arsenic protects animals from arsenic induced oxidative stress and reduce body arsenic burden (49). Exposure of rats to arsenie (2.5 mg/kg, intraperitoneally for 6 weeks) increases the levels of tissue reaetive oxygen species (ROS), metallothionein (MT) and thiobarbitnrie aeid reaetive substance (TEARS) and is accompanied by a decrease in the aetivities in the antioxidant enzymes such as superoxide dismutase (SOD), eatalase and glutathione peroxidase (GPx). Also, Arsenic exposed mice exhibits hver injury as reflected by reduced acid phosphatase (AGP), alkaline phosphatase (ALP) and aspartate aminotransferase (AST) activities and altered heme synthesis pathway as shown by inhibited blood 8-aminolevulinic acid dehydratase (5-ALAD) activity. Co-administration of M. oleifera seed powder (250 and 500 mg/kg, orally) with arsenie significantly increases the activities of SOD, catalase, GPx with elevation in redueed GSH level in tissues (liver, kidney and brain). These ehanges are accompanied by approximately 57%, 64% and 17% decrease in blood ROS, liver metallothionein (MT) and lipid peroxidation respectively in animal eo-administered with M. oleifera and arsenic. There is a reduced uptake of arsenie in soft tissues (55% in blood, 65% in liver, 54% in kidneys and 34% in brain) following eo-administration of M. oleifera seed powder (particularly at the dose of 500 mg/kg). This points to the fact that administration of M. oleifera seed powder could be beneficial during chelation therapy with a thiol chelator (26). 

Dalton, T.P., Q. Li, D. Bittel, L. Liang and G.K. Andrews. Oxidative stress activates metal-responsive transcription factor-1 binding activity. Occupancy in vivo of metal response elements in the metallothionein-I gene promoter. J. Biol. Chem. 271 26233—26241, 1996. 

Viarengo, A., B. Burlando, M. Cavaletto, B. Marchi, E. Ponzano and J. Blasco. Role of metallothionein against oxidative stress in the mussel Mytilus galloprovincialis. Am. J. Physiol. 277 R1612 R1619, 1999. 

Dalton TP, Paria BC, Fernando LP, Huet-Hudson YM, Dey SK and Andrews GK (1997) Activation of the chicken metallothionein promoter by metals and oxidative stress in cultured cells and transgenic mice. Comp Biochem Physiol B Biochem Mol Biol 116 75 -86. 

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