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Biometals (2010) 23:897926 DOI 10.1007/s10534-010-9351-z
Role of metallothionein in cadmium trafc and toxicity in kidneys and other mammalian organs
Ivan Saboli Davorka Breljak Mariokarica
Carol M. Herak-Kramberger
Received: 30 November 2009 / Accepted: 28 May 2010 / Published online: 15 June 2010 Springer Science+Business Media, LLC. 2010
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 ltered, endocytosed in the proximal tubule cells, and degraded in lysosomes. Liberated Cd can immediately affect the cell structures and functions. The resulting protein-uria and CdMT in the urine can be used as biomarkers of tubular injury.
Keywords Antioxidants Heavy metals
Hepatotoxicity Nephrotoxicity Oxidative stress
Reactive oxygen species Urine metallothionein
AbbreviationsApo-MT Metallothionein protein not complexed with metalBBM Brush-border membraneBLM Basolateral membraneDMT-1 Divalent metal transporter 1 GIF Growth inhibitory factor (MT-3) GSH Reduced glutathioneGSSG Oxidized glutathioneMT MetallothioneinMTF-1 Metalloregulatory transcription factor 1MT-null mice MT-1 and MT-2 knock out mice Oat Organic anion transporter
I. Saboli (&) D. Breljak M.karica
C. M. Herak-KrambergerUnit of Molecular Toxicology, Institute for Medical Research and Occupational Health, Ksaverska cesta 2, 10001 Zagreb, Croatiae-mail: [email protected]