Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology
ReviewZinc, antioxidant systems and metallothionein in metal mediated-apoptosis: Biochemical and cytochemical aspects
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.
References (153)
- et al.
Morphological and biochemical characterization and analysis of apoptosis
J. Pharmacol. Toxicol. Methods
(1997) - et al.
Expression of the mouse metallothionein-I and -II genes provides a reproductive advantage during maternal dietary Zn deficiency
J. Nutr.
(1999) - et al.
Induction of metallothionein by steroids in rat primary hepatocyte cultures
Toxicol. Appl. Pharmacol.
(1987) - et al.
The physiological role of zinc as an antioxidant
Free Radic. Biol. Med.
(1990) - et al.
Newly delivered transferrin iron and oxidative cell injury
FEBS Lett.
(1997) - et al.
Oxidative stress as a mediator of apoptosis
Immunol. Today
(1994) - et al.
Reversible Zn exchange between metallothionein and the estrogen receptor Zn finger
FEBS Lett.
(1996) - et al.
Metallothioneins in human tumors and potential roles in carcinogenesis
Mutat. Res.
(2003) - et al.
A role for extracellular metallothioneins in CNS injury and repair
Neuroscience
(2004) - et al.
Metallothionein expression in animals: a physiological perspective on function
J. Nutr.
(2000)
Redox regulation of copper-metallothionein
Arch. Biochem. Biophys.
Metallothionein transfers Zn to mitochondrial aconitase through a direct interaction in mouse hearts
Biochem. Biophys. Res. Commun.
The orchestration of body iron intake: how and where do enterocytes receive their cues?
Blood Cells, Mol. Dis.
The human ZIP1 transporter mediates zinc uptake in human K562 erythroleukemia cells
J. Biol. Chem.
Transcriptional induction of metallothionein-I and -II genes in the livers of Cu,Zn-superoxide dismutase knockout mice
Biochem. Biophys. Res. Commun.
Phorbol ester-induced cell death in PC-12 cells overexpressing Bcl-2 is dependent on the time at which cells are treated
Cell Biol. Int.
Differential oxidation of thioredoxin-1, thioredoxin-2, and glutathione by metal ions
Free Radic. Biol. Med.
Signaling events for metallothionein induction
Mutat. Res.
Roles of the metallothionein family of proteins in the central nervous system
Brain Res. Bull.
Effects of copper ions on the free radical-scavenging properties of reduced glutathione: implications of a complex formation
J. Trace Elem. Med. Biol.
Metallothionein-null mice express altered genes during development
Biochem. Biophys. Res. Commun.
Identification and functional expression of HAH1, a novel human gene involved in copper homeostasis
J. Biol. Chem.
Annexin V for flow cytometric of phophatidylserine expression on B cells undergoing apoptosis
Blood
New evidence of iron and zinc interplay at the enterocyte and neural tissues
J. Nutr.
Nitric oxide destroys zinc–sulfur clusters inducing zinc release from metallothionein and inhibition of the Zn finger-type yeast transcription activator LAC9
Biochem. Biophys. Res. Commun.
Enhanced sensitivity to oxidative stress in cultured embryonic cells from transgenic mice deficient in metallothionein I and II genes
J. Biol. Chem.
The role of iron in cell cycle progression and the proliferation of neoplastic cells
Biochim. Biophys. Acta
Isolation of a murine copper transporter gene, tissue specific expression and functional complementation of a yeast copper transport mutant
Gene
Transgenic mice that overexpress metallothionein-I are protected from cadmium lethality and hepatotoxicity
Toxicol. Appl. Pharmacol.
Susceptibility of MT-null mice to chronic CdCl2-induced nephrotoxicity indicates that renal injury is not mediated by the CdMT complex
Toxicol. Sci.
Down-modulation of CD4 antigen during programmed cell death in U937 cells
FEBS Lett.
Metallothionein/disulfide interactions, oxidative stress, and the mobilization of cellular zinc
Neurochem. Int.
Novel mechanisms of natural antioxidant compounds in biological systems: involvement of glutathione and glutathione-related enzymes
J. Nutr. Biochem.
Metal donation and apo-metalloenzyme activation by stable isotopically labeled metallothionein
Mar. Environ. Res.
Antioxidant enzymes and human diseases
Clin. Biochem.
Effect of systemic zinc administration on delayed neuronal death in the gerbil hippocampus
Brain Res.
A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation
Mol. Cell
Increased apoptosis in a variety of tissues of zinc-deficient rats
Life Sci.
Protective effect of metallothionein against the toxicity of cadmium and other metals
Toxicology
Activation of nuclear factor kappaB: potential role in metallothionein-mediated mitogenic response
Cancer Res.
Zinc ions prevent processing of caspase-3 during apoptosis induced by geranylgeraniol in HL-60 cells
J. Biochem.
Inflammation in central nervous system injury
Philos. Trans. R. Soc. Lond., B Biol. Sci.
Protection against chemically-induced oxidative gastrointestinal tissue injury in rats by bismuth salts
Dig. Dis. Sci.
Functions of zinc in signalling, proliferation and differentiation of mammalian cells
BioMetals
Differential regulation and expression of stress proteins and ferritin in human monocytes
J. Cell. Physiol.
DNA-dependent protein kinase is one of a subset of autoantigens specifically cleaved early during apoptosis
J. Exp. Med.
Regulation of caspase activation and apoptosis by cellular zinc fluxes and zinc deprivation: a review
Immunol. Cell Biol.
Zinc and vitamin A supplementation in Indigenous Australian children hospitalised with lower respiratory tract infection: a randomised controlled trial
Med. J. Aust.
Catalytic selenols couple the redox cycles of metallothionein and glutathione
Eur. J. Biochem.
Nuclear localization of metallothionein during cell proliferation and differentiation
Cell. Mol. Biol.
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