Role of cytosolic copper, metallothionein and glutathione in copper toxicity in rat hepatoma tissue culture cells

Steinebach, O.M.; Wolterbeek, H. Th.

doi:10.1016/0300-483x(94)90168-6

Cited by 80 publications

(41 citation statements)

References 29 publications

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“…Although GSHmetal complexes have been identified in mammalian cells, and depletion of GSH sensitizes animals (18)(19)(20), phytochelatins have not been identified in animal systems. The basic biological distribution and spectral, chemical, and photochemical properties of native and synthetic phytochelatin complexes were reviewed recently (4).…”

Section: Sequestration Moleculesmentioning

confidence: 99%

Mechanisms for protection against copper toxicity

Dameron¹,

Harrison²

1998

The American Journal of Clinical Nutrition

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Essential transition metals such as copper, molybdenum, and zinc and nonessential metals like cadmium, mercury, and lead can be toxic at the cellular, tissue, and organ levels when present in excess. To avoid metal-induced toxicity most organisms use a redundant combination of metal-regulated import inhibition, sequestration, and enhanced export mechanisms. Combinations of these mechanisms are used to form detoxification pathways controlled through metal-binding proteins at transcriptional, translational, or enzymatic levels. In mammalian pathways copper is partially detoxified by sequestration in the metal-binding metallothioneins or export via the copper-translocating ATPases. Copper regulation of these two mechanisms is afforded by specific conformational changes induced in regulatory proteins on metal binding.Am J Clin Nutr 1998(suppl);67:1091S-7S. KEY WORDSCopper toxicity, detoxification mechanisms, minerals, essential elements, metallothionein, Menkes syndrome, Wilson disease, copper ATPase, phytochelatins INTRODUCTIONTransition metals such as copper, molybdenum, and zinc are essential to life because of the catalytic and structural roles they play in proteins and other biomolecules. Excessive concentrations of essential metal ions and nonessential metal ions like cadmium, mercury, and lead can be toxic at the cellular, tissue, and organ levels. Most organisms use a redundant array of cellular mechanisms to limit the toxicity of metal ions. Many of these detoxification mechanisms are not entirely specific and are used for a variety of metals. The purpose of this review is to discuss intracellular mechanisms used to metabolize excessive concentrations of copper. The emphasis of the article will be directed toward the development of appropriate detoxification pathways and mechanistic models for mammalian cell types. In the course of developing mammalian models it will be necessary to discuss the model pathways and mechanisms by which a selection of other organisms detoxify copper and other transition elements. The detoxification of copper will be compared and contrasted with that of cadmium, which shares some of the same mechanisms. The central questions being approached in these model pathways are, which mechanisms are utilized and, if the mechanism is specific for copper, how is the specificity generated? General mechanismsA selection of the cellular mechanisms used by cells to detoxify metals are presented in Figure 1 to show the scope of mechanisms used by diverse organisms. Simplistically, the detoxification systems can be subdivided into reduction of metal uptake, enhanced metal exportation, and metal sequestration mechanisms.The reduction of metal importation to limit toxicity can operate through inhibition of the import machinery for the metal or by making the extracellular metal unavailable for absorption. For example, the amount of iron taken up by mammalian cells is partially regulated by controlling the membrane concentration of the receptor for the iron-transport protein transferrin at t...

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Section: Sequestration Moleculesmentioning

confidence: 99%

Mechanisms for protection against copper toxicity

Dameron¹,

Harrison²

1998

The American Journal of Clinical Nutrition

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“…Studies by Stacey and Klaassen (1981) indicated that Cu> decreases GSH concentration in rat hepatocytes. In a study using rat hepatoma cells, Steinbach and Wolterbeek (1994) observed that Cu> is complexed by GSH immediately after entering the cell and that depletion of GSH almost instantaneously results in enhanced cellular toxicity. FIG.…”

Section: Discussionmentioning

confidence: 97%

Glutathione and Metallothionein Status in an Acute Response by Mercenaria mercenaria Brown Cells to Copper in Vivo

Zaroogian

Norwood

2002

Ecotoxicology and Environmental Safety

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“…19) Therefore, binding of Cu to MT appears to render Cu redox-inactive, but oxidation of free thiols critical for metal binding can reduce MT/ Cu interactions and potentiate Cu redox cycling. 18) If Cu is released from accumulated MT in Cd-MT accumulated mice, this free Cu in turn might enhance the release of Cd from its binding to MT.…”

Section: )mentioning

confidence: 99%