Role of metallothionein in cadmium traffic and toxicity in kidneys and other mammalian organs |
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Authors: | Ivan Saboli? Davorka Breljak Mario ?karica Carol M Herak-Kramberger |
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Institution: | (1) Unit of Molecular Toxicology, Institute for Medical Research and Occupational Health, Ksaverska cesta 2, 10001 Zagreb, Croatia;(2) Present address: School of Medicine, Department of Microbiology and Immunology, Autoimmunity Center, Temple University, Philadelphia, PA 19140, USA |
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Abstract: | Metallothioneins are cysteine-rich, small metal-binding proteins present in various mammalian tissues. Of the four common
metallothioneins, MT-1 and MT-2 (MTs) are expressed in most tissues, MT-3 is predominantly present in brain, whereas MT-4
is restricted to the squamous epithelia. The expression of MT-1 and MT-2 in some organs exhibits sex, age, and strain differences,
and inducibility with a variety of stimuli. In adult mammals, MTs have been localized largely in the cell cytoplasm, but also
in lysosomes, mitochondria and nuclei. The major physiological functions of MTs include homeostasis of essential metals Zn
and Cu, protection against cytotoxicity of Cd and other toxic metals, and scavenging free radicals generated in oxidative
stress. The role of MTs in Cd-induced acute and chronic toxicity, particularly in liver and kidneys, is reviewed in more details.
In acute toxicity, liver is the primary target, whereas in chronic toxicity, kidneys are major targets of Cd. The intracellular
MTs bind Cd ions and form CdMT. In chronic intoxication, Cd stimulates de novo synthesis of MTs; it is assumed that toxicity
in the cells starts when loading with Cd ions exceeds the buffering capacity of intracellular MTs. CdMT, released from the
Cd-injured organs, or when applied parenterally for experimental purposes, reaches the kidneys via circulation, where it is
filtered, endocytosed in the proximal tubule cells, and degraded in lysosomes. Liberated Cd can immediately affect the cell
structures and functions. The resulting proteinuria and CdMT in the urine can be used as biomarkers of tubular injury. |
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