Mechanisms for protection against copper toxicity

Abstract

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...

Vertebrate Ctr1 coordinates morphogenesis and progenitor cell fate and regulates embryonic stem cell differentiation

“…1 C and D, compare lanes 4, 5, and 6). Consistent with the observation that high levels of intracellular copper induce the expression of the metallothionein gene (26), treatment of animal caps with solutions of copper sulfate that had no effect on either cell fate or morphogenesis resulted in strong metallothionein expression ( Fig. 1 B-E).…”

Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper

“…Changes in multiple MT genes (MT1A, MT1B, MT1E, MT1F, MT1G, MT1J, MT1K, MT1X, and MT2A) were observed at low copper concentrations at all exposure times. To maintain homeostatic levels of copper, cells use a combination of metal-regulated import, export, and sequestration mechanisms (15). In most organisms, MTs play central roles in the homeostasis of essential metals such as zinc and copper (17,24,66).…”

Molecular characterization of an operon, cueAR, encoding a putative P1-type ATPase and a MerR-type regulatory protein involved in copper homeostasis in Pseudomonas putida The GenBank accession number for the sequence reported in this paper is AF390440.

“…It is estimated that over 50 % of all proteins are metalloproteins and that about a third of all structurally characterized proteins contain metals (Degtyarenko, 2000). Copper is one such element that is required for a number of important cellular enzymes such as cytochrome oxidase, superoxide dismutase, ascorbate oxidase, ceruloplasmin, laccase, lysyl oxidase and other oxygenases (Camakaris et al, 1999 ;Buffoni & Ignesti, 2000 ;Dameron & Harrison, 1998). However, excess cellular copper can react non-specifically with cysteine and histidine residues in proteins and disrupt their activity.…”

“…However, excess cellular copper can react non-specifically with cysteine and histidine residues in proteins and disrupt their activity. Copper is also known to produce reactive oxygen species, which can lead to cellular damage (Dameron & Harrison, 1998) The GenBank accession number for the sequence reported in this paper is AF390440. intracellular copper at subtoxic levels, as it is extremely toxic at supra-optimal concentrations.…”

“…Eukaryotic and prokaryotic systems possess several mechanisms for copper homeostasis, such as reduced influx, facilitated efflux, sequestration and modification (Camakaris et al, 1999 ;Dameron & Harrison, 1998). In eukaryotes, many transition metals, including copper, are generally sequestered by small cysteine-rich proteins termed metallothioneins.…”