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

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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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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

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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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  1. Mario Škarica

    Present address: School of Medicine, Department of Microbiology and Immunology, Autoimmunity Center, Temple University, Philadelphia, PA, 19140, USA

Authors and Affiliations

  1. Unit of Molecular Toxicology, Institute for Medical Research and Occupational Health, Ksaverska cesta 2, 10001, Zagreb, Croatia

    Ivan Sabolić, Davorka Breljak, Mario Škarica & Carol M. Herak-Kramberger

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  1. Ivan Sabolić
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  2. Davorka Breljak
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Correspondence to Ivan Sabolić.

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Sabolić, I., Breljak, D., Škarica, M. et al. Role of metallothionein in cadmium traffic and toxicity in kidneys and other mammalian organs. Biometals 23, 897–926 (2010). https://doi.org/10.1007/s10534-010-9351-z

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