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BioMetals

, Volume 23, Issue 5, pp 897–926 | Cite as

Role of metallothionein in cadmium traffic and toxicity in kidneys and other mammalian organs

  • Ivan SabolićEmail author
  • Davorka Breljak
  • Mario Škarica
  • Carol M. Herak-Kramberger
Article

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.

Keywords

Antioxidants Heavy metals Hepatotoxicity Nephrotoxicity Oxidative stress Reactive oxygen species Urine metallothionein 

Abbreviations

Apo-MT

Metallothionein protein not complexed with metal

BBM

Brush-border membrane

BLM

Basolateral membrane

DMT-1

Divalent metal transporter 1

GIF

Growth inhibitory factor (MT-3)

GSH

Reduced glutathione

GSSG

Oxidized glutathione

MT

Metallothionein

MTF-1

Metalloregulatory transcription factor 1

MT-null mice

MT-1 and MT-2 knock out mice

Oat

Organic anion transporter

PT

Proximal tubules

RE

Response element

RNS

Reactive nitrogen species

ROS

Reactive oxygen species

ZnMT

CdMT or CuMT, metallothionein complexed with Zn, Cd or Cu, respectively

Notes

Acknowledgements

The authors thank Mrs. Eva Heršak for technical assistance in performing experiments. This work was supported by grant 022-0222148-2146 from Ministry for Science, Education and Sports, Republic of Croatia (I.S.).

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Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Ivan Sabolić
    • 1
    Email author
  • Davorka Breljak
    • 1
  • Mario Škarica
    • 1
    • 2
  • Carol M. Herak-Kramberger
    • 1
  1. 1.Unit of Molecular Toxicology, Institute for Medical Research and Occupational HealthZagrebCroatia
  2. 2.School of Medicine, Department of Microbiology and Immunology, Autoimmunity CenterTemple UniversityPhiladelphiaUSA

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