Cadmium metallothionein complex

The binding of cadmium to metallothionein decreases toxicity to the testes but increases the nephrotoxicity, possibly because the complex is preferentially, and more easily, taken up by the kidney than the free metal. Dosing animals with the cadmium-metallothionein complex leads to acute kidney damage, whereas exposure to single doses of cadmium itself does not. 

Cadmium (Cd) is a non-essensial metal used in industry as an anti-corrosive agent, and is found as a contaminant in food and also in cigarette smoke. The most serious consequence of chronic Cd poisoning is lung- and prostate cancer but the first effect during chronic intake is kidney damage, manifested by marked proteinuria [164]. Under chronic exposure, cadmium is primarily taken up by the liver, where it induces synthesis of metallothionein (MT) and induces formation of cadmium-metallothionein complexes. 

Cd(II) can bind to both the bases and the phosphate groups of DNA, and tends to destabilize the DNA helix (Jacobson and Turner 1980). However, these effects do not constitute DNA damage in the usual sense of the term (i.e., strand breaks, cross-links, adducts). Incubation of DNA with Cd(II) alone or with H2O2 did not result in strand breaks (Roy and Rossman, unpublished data). Cadmium-metallothionein complex is able to induce DNA strand breaks (Muller et al. 1991). However, the production of DNA strand breaks in cells by a cadmium-metallothionein complex is unlikely. Pretreatment of cells with Zn(II) to induce metallothionein resulted in decreased toxicity and DNA strand breaks by Cd(II) (Coogan et al. 1992). Transfection of a metallothionein overproducing plasmid into G12 cells abolished the mutagenicity of Cd(II) (Goncharova and Rossman, in preparation). 

Mecfianisni of toxicologic damage. Cadmium induces the formation of metallothionein and binds to it in the tissues. The cadmium-metallothionein complex promotes renal accumulation. Metabolism releases free cadmium, which is nephrotoxic. 

Cadmium, like zinc, binds to a protein, metallothionein, in the body The presence of cadmium increases the production of this protein by many times (the body increases detoxication, when threatened, which may be a reason for the development of tolerance). Although the binding removes the cadmium and effectively detoxifies it, the cadmium-protein complex is deposited in the kidneys and cadmium is eventually released, whereupon it seriously damages the organ. 

CdMT cadmium-metallothionein DISC death inducing signaling complex... 

Placental metallothionein binds zinc and copper as well as cadmium. Zinc and copper are essential nutrients for the fetus whereas cadmium is toxic to the fetus and retained rather than transferred to the fetus. There is a question, therefore, as to how the essential metals are preferentially transported to the fetus while the toxic metal, cadmium, is retained. One possibility is that there is a greater sensitivity for zinc and copper metallothionein than cadmium metallothionein to the action of proteolytic enzymes present in trophoblasts. Degradation of the zinc and copper metallothionein complex facilitates the release of these metals to fetal blood, whereas cadmium metallothionein is resistant to this effect. 

Gabard B (1976) Improvement of oral chelation treatment of methyl mercury poisoning in rats. Acta Pharmacol Toxicol (Copenh) 39 250-255 Gale GR, Smith AB, Atkins LM, Jones MM (1985) Effects of diethyldithiocarbamate and N-methyl-N-dithiocarboxyglucamine on murine hepatic cadmium metallothionein in vitro. Res Commun Chem Pathol Pharmacol 49 423-434 Gale GR, Smith AB, Jones MM, Singh PK (1992) Evidence of active transport of cadmium complexing dithiocarbamates into renal and hepatic cells in vivo. Pharmacol Toxicol 71 452-456... 

Munoz, A., Laib, F., Petering, D.H. and Shaw, C.F. Ill (1999) Characterization of the cadmium complex of peptide 49-61 a putative nudeation center for cadmium-induced folding in rabbit liver metallothionein IIA. Journal of Biological Inorganic Chemistry, 4, 495—507. 

Thioneins are apoproteins that are exceptionally sulfur-rich (composed of greater 30 mol% cysteine). These proteins are found in high abundance in liver and kidney cytoplasm where they form metallothioneins (the holo-protein forms) upon complexation with metal ions. Thi-onein synthesis is induced by the presence of metals, especially zinc, copper, mercury, and cadmium. 

Lopez, M.J., Arino, C., Dfaz-Cruz, S., Dfaz-Cruz, J.M., Tauler, R., and Esteban, M., Voltammetry assisted by multivariate analysis as a tool for complexation studies of protein domains competitive complexation of a and /J-metallothionein domains by cadmium and zinc, Environ. Sci. Technol., 37, 5609-5616, 2003. 

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