Metallothionein cadmium toxicity role

Deeds, J.R., and Klerks, P.L. (1999) Metallothionein-like proteins in the freshwater oligochaete Limnodrilis udekemianus and their role as a homeostatic mechanism against cadmium toxicity. Environ. Pollut. 106, 381-389. 

Wahba ZZ, Coogan TP, Rhodes SW, et al. 1993. Protective effects of selenium on cadmium toxicity in rats Role of altered toxicokinetics and metallothionein. J Toxicol Environ Health 38(2) 171-182. 

Bakka A, Samarawickrama GP, Webb M (1981) Metabolism of zinc and copper in the neonate Effect of cadmium administration during late gestation in the rat on the zinc and copper metabolism of the newborn. Chem.-Biol. Interact. 34 161-171 Bakka A, Webb M (1981) Metabolism of zinc and copper in the neonate Changes in the 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. Pharmcol. 54 148-155 Bremner J (1978) Cadmium toxicity Nutritional influences and the role of metallothionein. Wld. Rev. Nutr. Diet. 32 165-197... 

Srivastava RC, Husain MM, Srivastava SK, et al. 1995. Effect of pre-exposure to cadmium and silver on nickel induced toxic manifestations in mice possible role of ceruloplasmin and metallothionein. Bull Environ Contam Toxicol 54 751-759. 

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). 

Endogenous substances other than metallothionein may be involved in minimizing the effects of heavy metals and excreting them from the body. Hepatic (liver) glutathione, discussed as a phase II conjugating agent in Section 7.4, plays a role in the excretion of several metals in bile. These include the essential metals copper and zinc toxic cadmium, mercury(II), and lead(II) ions and organometallic methyl mercury. 

Goyer RA, Cherian MG. Role of metallothionein in human placenta and rats with cadmium exposure. In Cadmium in the human environment toxicity and carcinogenicity. Nordberg G, Herber R,Alessio E (editors). International Agency for Research on Cancer (lARC) Scientific Publications, Vol 118, Eyon 1992 p. 239-247. 

Trace metal disturbances may be due to the uremia per se. Indeed, as the urinary excretion route is an important pathway of elimination of many trace elements, i.e. silicon, strontium, aluminum,... impairment of the kidney will be an important determinant of their accumulation, whilst in the presence of a reabsorptive defect a number of trace elements, especially those that are reabsorbed because of their essential role, be lost resulting in a deficient state. The presence of proteinuria may reasonably result in losses of protein bound elements. It has also been shown also that residual renal funchon may importantly alter the accumulation and hence toxic effects of aluminum [2]. In uremia translocation of a particular metal from one tissue to another may also occur. As an example, under normal circumstances the kidney is an important target organ for cadmium. In chronic renal failure however, possibly as a consequence of a reduction in binding proteins (e.g. metallothionein), the concentrahon of cadmium in this tissue decreases to extremely low levels which... 

The affinity of liver and kidney for a number of chemicals is also considerable. A protein in the liver, ligandin, has a remarkable degree of affinity for organic acids it plays a role in the transfer of these chemicals from blood into liver. Both liver and kidney may become storage depots for metals, like cadmium and zinc, due to the presence of small binding proteins called metallothioneins. When the binding capacity of these proteins is exceeded, local toxicity may appear, as is the case for cadmium in the kidney. 

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. 

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. 

Webb M, Magos L, Holt D (1980) The in vivo effects of maleate on the cation-distribution in rat kidney metallothionein subfractions after induction by cadmium and/or mercury. Chem. Biol. Interact. 32 137-149 Webb M (1982) Role of metallothioneins and other binding proteins in the renal handling and toxicity of metals. Proc. Internat. Symp. Nephrotoxicity (Guildford). Sept. 1981, London, Wiley-Heyden, pp. 296-309 Webb M, Cain K (1982) Commentary. Functions of Metallothionein. Biochem. Pharmacol. 31 137-142... 

Goyer RA (1991) Toxic effect of metals. In Amdur MO, Doull J, Klaassen CD (eds) Casarett and Doull s toxicology, the basic science of poisons, 4th edn. McGraw-Hill Pergamon, New York, pp 623-680 Goyer RA, Cherian MG (1992) Role of metallothionein in human placenta and rats exposed to cadmium. In Nordberg GF, Herber RFM, Alessio L (eds) Cadmium in the human environment. I ARC, Lyon, pp 239-247 Gregus Z, Watkins JB, Thompson TN, Klaassen CD (1982) Resistance of some phase II biotransformation pathways to hepatotoxins. J Pharmacol Exp Ther 222 471-479... 

Metallothionein (MT) is a low-molecular-weight metal-binding protein well known to toxicologists who study metals. The protein is believed to play an important role in the homeostasis of the essential micronutrients zinc and copper, but also influences the metabolism and toxicity of other metals, such as cadmium, mercury, and copper. 

There are at least three major types of natural proteins and peptides which are rich in cysteinyl residues metallothioneins, zinc finger proteins, and phytochelatins. The biological role and structural characteristics of metallothioneins are dealt with in Chapter 11 of this book. Zinc finger peptides are possible targets for cadmium(ll) toxicity, while phytochelatins play an important role in the defense mechanisms of plants (Chapter 13). The multicysteine peptides are frequently used to mimic the cadmium(ll) binding ability of all these natural substances. 

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