Copper and carcinogenesis

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Abstract

Metal ions play an important role in biological systems, and without their catalytic presence in trace or ultratrace amounts many essential co-factors for many biochemical reactions would not take place. However, they become toxic to cells when their concentrations surpass certain optimal (natural) levels. Copper is an essential metal. Catalytic copper, because of its mobilization and redox activity, is believed to play a central role in the formation of reactive oxygen species (ROS), such as O2radical dot and radical dotOH radicals, that bind very fast to DNA, and produce damage by breaking the DNA strands or modifying the bases and/or deoxyribose leading to carcinogenesis. The chemistry and biochemistry of copper is briefly accounted together with its involvement in cancer and other diseases.

Introduction

Copper is found in metal proteins since evolutionary times. Bucholz in 1816 reported that copper occurs in plant and animal tissues [1]. Later, in 1981, it was reported that copper-deficient rats developed anemia [1]. A great number of biologically active centers contain metals. The metal ion centers create the binding catalytic sites for biological function or toxicity [2]. Each metal ion imposes a specific interaction property to the biological molecule [3], [3](a), [3](b). Copper is an essential trace element for the human diet, required for enzymes and occurs in human and animal tissues in biological systems in both the +1 and +2 valence states [4]. The major functions of copper–biological compounds involve oxidation–reduction reactions in which copper containing biological molecules react directly with molecular oxygen [5], [6] to produce free radicals. The copper ion, the second most important ion that may participate in oxygen-dependent deleterious reactions in vivo, is also an integral part of many metalloenzymes [7], such as caeruloplasmin, cytochrome oxidase, superoxide dismutase [8], ascorbate oxidase and tyrosinase. There are 80 mg copper in total in adult humans (higher concentration in liver and brain) and with vitamins A, E and C decreases the toxicity of O2. It is known that the superoxide anion (O2radical dot) is the major reactive oxygen species (ROS) generated in mitochondria, which produces hydrogen peroxide (H2O2). In the presence of transition metal ions, such as iron, as well as copper, the hydrogen peroxide leads to the formation of the highly reactive hydroxyl radicals (O2radical dot and radical dotOH) [9], which can induce DNA and membrane damage. Furthermore, copper attached to the N-terminus of human albumin or amino acids (Asp-Ala-His-Lys) is not prevented from reacting with H2O2 or O2radical dot to form OHradical dot or other reactive species, resulting in site-specific damage [10]. In this paper an attempt is made to search and analyse the copper chemistry and the copper-binding to centers of biological interest [11] and modify biological function in tissue [12]. Moreover, it was analyzed its involvement in toxicity and oxidative damage in DNA and cancer [13], [14]. Thus, the effects of excess production of free radicals may play a role in the progression of cancer [15], through DNA damage.

Section snippets

The stereochemistry and coordination chemistry of copper

Copper from cuprum, Cu is the 29th element of the Periodic Table with electronic configuration 3d10 4s1. It is thus a post-transition element, beyond the d-block elements. Cu(I) therefore is with a completed 3d10 shell and Cu(II) loosing 2 electrons has 3d9 configuration and behaves as a transition element with a partially-filled d-block. The masses of the natural isotopes are 63 (69.17%) and 65 (30.83%). It is found in earth's crust 55 ppm and in seawater in a concentration of 3×10−3 mg/l. It

Toxicity and biological roles of copper

Copper in the form of bivalent ion, Cu2+ is very poisonous to lower organisms. For example, bacteria and other decay microorganisms die in water in a copper vessel, and copper compounds in general prevent growth of algae. Copper(II) compounds induce vomiting in human beings. A 5% copper sulfate solution can be used as an emetic for general poisoning. Copper(II) acetate, Cu(CH3COO)2·H2O is soluble in water and it is used as a mild caustic in medicine. Furthermore, copper(II) hydroxide, Cu(OH)2,

Copper–nucleotide interactions and copper–DNA adducts

Copper has been found to affect the cleaving double-stranded DNA in the presence of reductants and hydrogen peroxides. Yamanoto and Kawanishi proposed this damage that is sequence dependent [30]. There are several studies on the nature of binding between copper ions and nucleotides. NMR studies [31] show the line broadening by bivalent copper ions in order to locate the binding sites. These studies can also be used to determine the configuration of the metal bound nucleotide. It has been found

Copper protein complexes

Copper is absorbed from the diet in the stomach most likely as complex with amino acids (histidine or peptides) [5]. Amino acids and albumin have high-affinity binding sites for copper ions. In the liver, copper is bound to protein caeruloplasmin. Albumin is an important extracellular antioxidant and it binds haem and copper ions. Caeruloplasmin is a protein of relatively high molecular mass of around 134 000 Dalton with six or seven copper ions per molecule. Caeruloplasmin is normally used to

Oxidative stress and copper involvement

Copper dependent oxidative damage can be prevented by chelation with the antioxidants dipeptides which with imidazole ring chelate copper. Copper-DNA adducts may be able to promote oxidative damage to DNA [8]. Redox active metal ions such as Fe and Cu play a role in the formation of ROS (Fenton reaction) in biological systems [4], [13]. H2O2 inactivates the pro-oxidant part of the enzyme CuZnSOD due to oxidation of the histidine active site and loss of copper ion. Thus, incubation of human

Conclusions

In conclusion, copper ions are able to combine and react with molecular oxygen (dioxygen) and/or oxygen-derived reactive species through Haber–Weiss-like reactions. The ability of copper to combine with hydroperoxyl anion radicals (O2radical dot)or hydroperoxyl radical (HO2radical dot), the hydroxyl radicals (radical dotOH) to form hydrogen peroxide (H2O2) and molecular oxygen (O2) under complex formation allows nature to control and handle oxygen chemistry in normal metabolic processes [2], [3], [3](a), [3](b). It has been

Reviewer (MA 350)

Prof. Gérard Vergoten, Cresimm.Ufr de Chimie, Bât. C, Université des Sciences et Technologies de Lille, F-59655 Villeneuve d'Ascq, France.

Prof. Theophilos Theophanides, was born in Kavala, Greece. He studied Industrial Chemistry at the University of Bologna (1957), Italy. He did the MA (1961) and PhD (1963) at the University of Toronto, Canada. Fellow Chemical Institute of Canada. He was Prof at the University of Montreal and National Technical University of Athens, Silver Metal of the French Academy of Medicine, Dr Honoris Causa, University of Reims. Editor of Journals and books. Author of over 250 scientific publications,

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    Prof. Theophilos Theophanides, was born in Kavala, Greece. He studied Industrial Chemistry at the University of Bologna (1957), Italy. He did the MA (1961) and PhD (1963) at the University of Toronto, Canada. Fellow Chemical Institute of Canada. He was Prof at the University of Montreal and National Technical University of Athens, Silver Metal of the French Academy of Medicine, Dr Honoris Causa, University of Reims. Editor of Journals and books. Author of over 250 scientific publications, author and co-author of books. His scientific interests are in coordination chemistry, bioinorganic chemistry, biomaterials and biospectroscopy.

    Assoc. Prof. Jane Anastassopoulou was born in Trikala, Greece. She studied Physics at University of Athens (1971). She did the PhD, as well as the Privat Dozent on Radiation Chemistry at National Technical University of Athens. The scientific interests include Radiation Chemistry, Free Radicals Chemistry, Biospectroscopy, Bioinorganic Chemistry, Metal ions-DNA interactions. Author of 120 scientific publications, Editor of books, Author or co-author of books.

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