Review
Zinc, antioxidant systems and metallothionein in metal mediated-apoptosis: Biochemical and cytochemical aspects

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Abstract

Copper, zinc and iron are essential metals for different physiological functions, even though their excess can lead to biological damage. This review provides a background of toxicity related to copper, iron and zinc excess, biological mechanisms of their homeostasis and their respective roles in the apoptotic process. The antioxidant action of metallothionein has been highlighted by summarizing the most important findings that confirm the role of zinc in cellular protection in relation to metallothionein expression and apoptotic processes. In particular, we show that a complex and efficient antioxidant system, the induction of metallothionein and the direct action of zinc have protective roles against oxidative damage and the resulting apoptosis induced by metals with redox proprieties. In addition, to emphasize the protective effects of Zn and Zn–MT in Cu and Fe-mediated oxidative stress-dependent apoptosis, some aspects of apoptotic cell death are shown. The most widely used cytochemical techniques also have been examined in order to critically evaluate the available data from a methodological point of view. The observations on the role of Zn and MT could potentially develop new applications for this metal and MT in biomedical research.

Introduction

Copper (Cu), zinc (Zn) and iron (Fe) are trace elements required for the function of various enzymes and other cellular proteins, and become toxic in the case of excessive intracellular accumulation (Dock and Vahter, 1999). Redox-active metals, such as Cu and Fe, which are involved in the production of free radicals, play an important role in the regulation and induction of apoptosis. Most likely, both the induction of metallothionein (MT) and the direct action of Zn have protective roles against oxidative damage. In addition, a complex and efficient antioxidant system blocks free radical damage and the resulting apoptosis.

This review will evaluate the biomolecular and cytochemical roles of Zn, MT and antioxidant systems on the toxic effects caused by excess of metal. In many laboratories both long- and short-term experiments have been performed in order to clarify the mechanism of action of Zn and to understand if this metal is effective in blocking or slowing down the development of apoptotic processes. The study of MT and Zn could also be useful for evaluating the pathological situations in which states of metal deficiency or overload exist.

Section snippets

Metal toxicity

Cu, Zn and Fe are trace elements required for the function of various enzymes and other cellular proteins, and become toxic in the case of excessive intracellular accumulation (Dock and Vahter, 1999). An initial common event in the action of all toxic metals seems to be the generation of oxidative stress that is characterized by: (a) depletion of intracellular antioxidants (largely GSH) and free-radical scavengers (vitamins E and C), (b) inhibition of the activity of various enzymes that

Antioxidant systems

The cells contain antioxidant molecules to defend against excess of ROS produced by accumulation of Cu or Fe.

In cells, a limited amount of ROS is produced in normal metabolic processes in the cytoplasm and peroxisomes, whereas the bulk of these substances is generated as a side product during oxidative phosphorylation in mitochondria (Turrens, 2003). In subtoxic concentrations, these products may act as second messengers in intracellular signal transduction pathways (Suzuki et al., 1997).

Zn–MT and apoptosis

Apoptosis represents an evolutionary conserved program of cell self-destruction by which cells are eliminated from a multicellular organism (Raff, 1998). Programmed cell death is a paradigm in which cells contain a genetically coded program of elements that lead to the death of cells. The biochemical and morphological events that effect apoptotic processes usually lead to a unique and highly controlled series of events (Kerr et al., 1972). This form of cell death is more analogous to “cell

Conclusion

This review examines some of the aspects surrounding the fields of metal toxicity, oxidative stress and consecutively apoptotic processes, and discusses the potential mechanisms by which Zn and MT can reduce metal toxicity and oxidative damage. Discussions of the various protective pathways that may be provided by the antioxidant network against heavy metal-mediated oxidative damage are addressed. Useful information for the understanding of the apoptotic process by cytochemical and enzymatic

Acknowledgments

This review is based on the data collected from our research and from more than 150 research papers and review articles. We apologize to those authors whose work we have not cited for space reasons. The authors are grateful to Dr John Lazo for providing the MT−/− and MT +/+ cells. We also thank Dr Marilena Aquino de Muro for proof-reading the English version of the manuscript.

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