transition metals. characteristics, properties and uses

CHEMICAL ENGINEERING METHODS AND TECHNOLOGY

TRANSITION METALS

CHARACTERISTICS, PROPERTIES AND USES

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TRANSITION METALS

CHARACTERISTICS, PROPERTIES AND USES

AJAY KUMAR MISHRA EDITOR

Nova Science Publishers, Inc. New York

Copyright 2012 by Nova Science Publishers, Inc. All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. For permission to use material from this book please contact us: Telephone 631-231-7269; Fax 631-231-8175 Web Site: http://www.novapublishers.com

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The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers use of, or reliance upon, this material. Any parts of this book based on government reports are so indicated and copyright is claimed for those parts to the extent applicable to compilations of such works. Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. Additional color graphics may be available in the e-book version of this book. Library of Congress Cataloging-in-Publication Data Transition metals : characteristics, properties and uses / editor, Ajay Kumar Mishra. p. cm. Includes index.

1. Transition metal alloys. I. Mishra, Ajay Kumar, 1965- TN693.T7T73 2011 661'.06--dc23

Published by Nova Science Publishers, Inc. New York

ISBN: (eBook)

CONTENTS

Preface vii

Chapter 1 Role of Reactivity of Transition Elements in Life 1Mohamed Fikry Ragai Fouda, Omar Mohamed Abdel-Salam and Afaf Ezzat

Chapter 2 Nonlinear Optical Properties of Transition Metal Nanoparticles Synthesized by Ion Implantation 63Andrey L. Stepanov

Chapter 3 Self-Organization of the Nanocrystalline Structure and Radiation Resistance of Structural Materials 119V. P. Kolotushkin and A. A. Parfenov

Chapter 4 Transition Metal Complexes of Schiff Base Ligands of 3-Formylsalicylic Acid: Synthetic Pathways and Useful Properties 165Saikat Sarkar and Kamalendu Dey

Chapter 5 Structural and Magnetic Characterization of Cu-Picolinate and Cu-Quinaldinate Molecular Systems 221Bogumia urowska

Chapter 6 Review: Transition Metals in Medicine 263Hanan F. Abdel-Halim

Chapter 7 Application of Transition Metals as Active Compounds in Separation Techniques 299Iwona Rykowska and Wiesaw Wasiak

Chapter 8 Chromium Pigment 327Mohammad Fikry Ragai Fouda , Hanan. F.Abdel-Halim and Samia Abdul Raouf Mostafa

Chapter 9 Transition Metals: Bioinorganic and Redox Reactions in Biological Systems 349Marisa G. Repetto and Alberto Boveris

Contents vi

Chapter 10 Hydrodesulfurization of Dibenzothiophene over Various CoMoP/Al2O3 Sulfide Catalysts Prepared from Co and Mo Phosphoric Acids 371Masatoshi Nagai, Yuki Nakamura and Shoji Kurata

Chapter 11 Mixed Transition Metal Acetylides with Different Metals Connected by Carbon-Rich Bridging Units: On the Way to Hetero-Multimetallic Organometallics 383Heinrich Lang and Alexander Jakob

Chapter 12 Reactivity of Unstable Chemicals in the Presence of Transition Metals 453Mieko Kumasaki

Index 483

PREFACE In this book, the authors present topical research in the study of the characteristics,

properties and uses of transition metals. Topics discussed include the nonlinear optical properties of transition metal nanoparticles synthesized by ion implantation; the structural and magnetic characterization of Cu-Picolinate and Cu-Quinaldinate molecular systems; application of transition metals as active compounds in separation techniques; the reactivity of unstable chemicals in the presence of transition metals and the bioinorganic and redox reactions in biological systems of transition metals. (Imprint: Nova)

Transition metals are commonly known as d-block elements that forms the bridge between the main group elements of the periodic table. These elements are lustrous / shiny solids or liquids and possess metallic properties which include hardness, toughness and strong metallic atom-atom bonding. Some of the characteristic properties of these metals include its ability to form colour compounds, exhibiting many oxidations states and their magnetic behaviour. Besides these properties, these metals are good conductors of heat and electricity and have many free electrons per atom to carry thermal and electrical energy. These metals can be easily hammered and bent into different shapes. Due to the strong metallic bonding, the transition elements show high melting point, boiling point and high density. Transition metals are used as alloy and useful as structural materials due to their strength and hardness properties. They are also used as pigments for artwork and give bright colours to stained glass and ceramic glazes.

Due to metallic properties, the transition metals have been exploited for many industrial, commercial, strategic, environmental, ornamental, medial, biomedical applications. Among these, the common use at technological scale is their use as catalysts in industrial chemical processes and also in the anti-pollution catalytic converters in car exhausts. Due to the catalysis behaviour of the transition metals, a variety of new synthetic methodologies has been developed and applied to industrial processes. It is very difficult to find a multi-step synthesis of complex organic molecules where transition metal catalyzed processes are not employed. Significant progress in homogeneous catalysis and the depth understanding of the mechanisms and also from developments based on the new information derived in studying the behaviour of organotransition metal complexes. The organotransition metal chemistry and homogeneous catalysis area has been extensively studied with the ferrocene, Ziegler catalyst, and the Hoechst-Wacker process. This prompted the organotransition metal chemistry in a significant increase in the number and novel chemical features that are applicable to catalysis. The advantage of homogeneous catalysis over conventional heterogeneous catalysis allows

Ajay Kumar Mishra viii

the clarification of the reaction mechanisms at the molecular level by catalytic cycles consisting of elementary processes.

Transition metals have a key role in the development of medicine, coordination chemistry, plant biology, materials science, polymer science and also by biochemists and biologists as well. The transition metals ions and complexes play a central role in controlling the reactivity and mechanism of the chemical reaction of interest. This can be due to the actual reaction occurring at the metal centre and/or the catalytic activity of the metal complex in an overall chemical process. The unique ability of transition metal ions and complexes to control the chemistry of environmental, industrial, and biological processes has increased the importance of clarifying their mechanistic behaviour in simple and complex chemical processes. The role of the central metal atom or ion has received considerable attention not only in fundamental inorganic and organometallic chemistry but also in more applied areas such as in environmental, bioinorganic, and bioorganic chemistry.

Transition metal catalyzed polymerization, synthesis of compounds of interest for material research, the use of non-conventional solvents such as water, supercritical fluids, and ionic liquids, and reactions employing polymer supported reactants have gained enormous attentions. The polymer synthesis has also been widely studied by the olefin polymerization and copolymerization by late transition metal catalysts. Polymer synthesis has been influenced by the development of single-site polymerization of olefins by complexes of the transition metals where the coordination and insertion modes of monomers are controlled by the ligand. Ring opening metathesis polymerization developed the studies of metal carbene type transition metal complexes. This methodology can be involved through studies on the elementary processes which can be applied to prepare new materials of unique properties for various applications.

This book covers the a wider domain of research and development where the use of transition metals have been investigated for various applications such as drug delivery, organometallics, bio-organometallic chemistry, chemotherapy, clinical and pharmaceutical aspects. This will enlighten the beginners by providing an excellent source of high quality information for experts in the field. This book will also allow the bioinorganic chemists, the pharmaceutical industry, chemists and biochemists to innovate their ideas using multidisciplinary approach and applications of transition metals.

The book covers broad literatures in the area of transition metals in organic synthesis including novel reactions, new catalysts, ligands, and reaction conditions and applications in synthesis of complex organic molecules. The book is especially beneficial to the scholars who are planning or are working towards their graduate and postgraduate degrees in this field of bioinorganic chemistry. The advance aspects of the bioinorganic chemistry is a platform for all levels of academics and research as it provides background for the recent research literature, abbreviation summaries of the inorganic chemistry, biochemistry and spectroscopy. The book is thus an interesting read for those who wish to obtain a general overview of the most important transition metals, fundamentals concept and also will provide a useful steppingstone for further exploration of the literature. The book also covers a wide research area that integrates biology, chemistry, materials science, engineering and nanotechnology to present an interdisciplinary approach for solving multitude problems. The unique approach to cover the fundamental knowledge along with the recent advancements for the research and development in the field of transition metals is sure to make a niche for extensive knowledge dissipation to all ages.

In: Transition Metals: Characteristics, Properties and Uses ISBN 978-1-61324-559-0 Editor: Ajay Kumar Mishra 2012 Nova Science Publishers, Inc.

Chapter 1

ROLE OF REACTIVITY OF TRANSITION ELEMENTS IN LIFE

Mohamed Fikry Ragai Fouda1, Omar Mohamed Abdel-Salam2

and Afaf Ezzat3 1Professor of Inorganic Chemistry, Department of Inorganic Chemistry,

National Research Centre, Cairo, Egypt 2Professor of Pharmacology, Department of Toxicology and Narcotics,

National Research Centre, Cairo, Egypt 3Professor of Biochemistry, Department of Nutrition and Food Sciences,

National Research Centre, Cairo, Egypt

INTRODUCTION In the last two decades, the field of biological inorganic chemistry has shown a rapid

explosion with a tremendous increase in our understanding of the roles of transition metals in both higher plants and human life. The 25 elements that have been shown to be essential to life in microorganisms are belonging to "s", 'b' and 'd' block elements. The "s" block elements are namely H, Na, B, K, Mg and Ca, whereas the "b" block elements are; C, N, O, F, Si, P, S, Cl, Se, I and As. The "d" block elements namely are V, Cr, Mn, Fe, Co, Ni, Cu and Mo, whereas the "d" closed shell elements are Zn and Cd. Amongst all the following four 'b" block elements, H, C, N and O are the most abundant elements in living organisms, where they make up 99.3% of all the atoms in the body, but the remaining 21 elements only account for 0.7 %.

Apart form the last four elements, which constitute the outermost percentage of elements essential for life, the remaining twenty one elements can be divided into two groups: (i) the macronutrients: these consist of seven elements; calcium, phosphorous, potassium, sulphur, chlorine, sodium and magnesium, which are found in greater concentrations in the body than are the remainder of the 21 elements; (ii) the trace elements: these consist of fourteen elements; iron, manganese, copper, zinc, molybdenum, cobalt, vanadium, chromium, nickel, fluorine, silicon, selenium, arsenic and iodine. All the 21 elements of the macronutrients and

Mohamed Fikry Ragai Fouda, Omar Mohamed Abdel-Salam et al. 2

the trace elements are found in living systems, either as ions, or covalently bonded to organic residues.

This monograph is confined to throw the light on the importance of V, Cr, Mn, Fe, Co, Ni, Cu, which are belonging to first transition series, as well as closed shell zinc element, in addition to molybdenum which is a member in the second transition series. This monograph is also oriented to clarify the importance of the elements mentioned before as micronutrients for higher plants and their participation in various enzyme systems in the plant. In that context the sources of these inorganic micronutrients in the soil is taken into consideration. In addition, it is aimed to explain the important role of these elements in body life, where they are able to create oxidative stress inside the body on one hand and the ability of them to act as antioxidants in case of attachment to some proteins, on the other hand.

Some of these metals are contained in several enzymes such as iron (transferrin), molybdenum (xanthine oxidase), vanadium (hemovanadin), zinc (carbonic anhydrase), and copper (hepatocuprein). There is also an evidence linking some diseases and the deficiency of a number of transition elements. At the same time, an increase in some of transition elements has been suggested to lead to neurodegenerative disorders e.g., iron in case of Parkinson's disease and copper in Alzheimer's disease. In addition, the so called metallo- therapeutics have been used in the last few decades in the treatment of some human aliments. The application of metallo-therapy includes the use of some organometallics or metal-organic complexes, such as using some gold and platinum complexes as antiarthritis and antitumour drugs, respectively. The metal-based photodynamically active compounds are in use nowadays in treatment of some types of human malignancies. Deficiency in the first raw transition elements as well as Zn and Mo leads to deficiency in enzymes containing them in the body. The excess amounts of these soft and borderline metals prefer to react with the soft bases e.g., glutathione and sulfur proteins which are considered antioxidants. The different phenomena showed by the aforementioned elements will be discussed in the light of affinity of their cations towards several anions.

TRANSITION METALS AND PLANTS The higher plants which are usually contain chlorophyll as a photosensitizer synthesize

their nutrients and tissues from simple substances from air and different constituents in the soil (e.g.CO2,O2, H2O, NO-3, SO-24, Cl-, Ca2+, Mg2+, Fe+2, Mn2+, CO2-3, etc.). These elements can be classified to three categories based on demands of them by plant. These categories are macro-micro- and benefitial nutrients [1, 2].

The macronutrients are those elements which are required for plant with a quantities ranged between few- and many hundreds of kilograms / hectare. These elements namely are, hydrogen, oxygen, nitrogen, carbon, phosphorous, calcium, magnesium and sulphur. Based on the electronic configuration of these elements one can be classified as "s" and "b" block elements [3].

On the other hand both micro- and beneficial elements (Mn, Fe, Co, Ni, Cu, Zn, Mo, B) are belonging to "d" block elements except B which belongs to "s" block elements.

The last two categories of elements are required for healthy plants, with a quantity ranged between few and several hundreds of grams/hectare. These elements have important roles in

Role of Reactivity of Transition Elements in Life 3

plants and microbial vital processes [4]. The most common ones of these roles especially their participation in the enzyme systems [see table (1)][2].

Table 1. Functions of several micronutrients in higher plants

Micronutrients Functions in higher plants Manganese Activates decarboxylase, dehydrogenase, and oxidase enzymes;

important in photosynthesis, nitrogen metabolism, and nitrogen assimilation.

Iron Present in several peroxidase, catalase, and cytochrome oxidase enzymes; found in ferredoxine which participates in oxidation reduction reactions (e.g. NO-3 and SO42- reduction, nitrogen fixation; important in chlorophyll.

Cobalt Essential for nitrogen fixation; found in vitamin B12. Nickel Required as a component of the urease enzyme. Zinc Present in several dehydrogenase, proteinase and peptidase

enzymes; promostes growth hormones and starch formation; promotes seed maturation and production.

Molybdenum Present in nitrogenase (nitrogen fixation) and nitrate reductase enzymes; essential for nitrogen fixation and high oxidizing.

Boron Activates certain dehydrogenase enymes; facilitates sugar translocation and synthesis of nucleic acids and plant hormones; essential for cell division and development.

Copper Present in laccase and several other oxidase enzymes; important in photosynthesis, protein and carbohydrate metabolism, and probably nitrogen fixation.

Based on these foregoing findings one can notices that macronutrient elements all among

the highly abundant elements in nature, where as micro- and beneficial elements are considered as ones from less common elements [3], except iron.

The requirements of higher plants for hard acidic ions such as Ca2+, K+, [PO2]1 can be gained from constituents of soil as well as from artificial fertilizers such as Ca(NO3)2, (NH4)2SO4, Ca (H2PO4)2, K2SO4, KNO3 etc. These fertilizers do not suffer from inconsistency in case if they applied in an alkaline soil.

The microand beneficial nutrients are considered as soft and borderline elements except Fe3+ and B3+.

The positive ions of these elements are being soft or borderline ones except Fe3+ and B3+ which are hard acidic species. Based on the foregoing discussions one can say that their bearing compounds are found as of insoluble compounds. The last ones are found in nature [3] according to the following:

Mn (Mn-oxides, silicates and carbonates); Fe (Fe-oxides, sulphides and silicates); Co(Co-sulphides and silicates); Ni (Ni-sulphides and silicates); Cu (Cu- sulphides, hydroxy carbonates and oxides); Zn (Zn-sulphides, carbonates, and silicates). The molybdenum may be found as sulphides, oxides and molybdates [3].


The previous forms are mostly insoluble so that they are converted to soluble salts (e.g. sulphates, nitrates) before application as fertilizers). In case of application of these salts as fertilizers in an alkaline soil, their ions suffer from inconsistancy and transformed to insoluble hydroxides. In such case these nutrients given to the plant in the form of metal- organic complexes stable at alkaline medium [4]. Here in the following one can find the nomenclature as well as chemical formulae and abbreviations of the most chelating agents used in preparation of the corresponding micro and beneficial metal organic complexes which derived from ethylencdiaminetelra acetic acid and its derivates as well as citric and oxalic acids: Ethylendiaminetetroacetic acid, (C10 H16 O8 N2, EDTA); Diethylemetriamepenta acetic acid (C14 H22 O12 N3); cyclohexanediaminetetroacetic (C14 H22 O8 N2, CDTA); Nitriloacetic acid (C6 H9 O6 N, HEDTA); Hydroxyethylemediaminetetroacetic acid (C10 H18 O7 N2); Ethylenediaminedichydroxyphenyl-acetic acid (C18 H20 O6 , EDDHA); Citric acid (C6 H8 O7 , CIT); Oxalic acid (C2 H2 O4,OX) [5].

CHEMICAL ELEMENTS IN LIFE Chemical elements essential to life forms can be divided into: (1) bulk elements (H, C, N,

O, P, S) which are present in large quantities; (2) macrominerals and ions; are those needed by the body in relatively large amounts; being composed of the "s" block elements Na, K, Ca, Mg and "p" block elements Cl and PO3- 4); (3) micro/trace minerals; are those needed in small amounts and consist of the d-block elements vanadium, chromium, molybdenum, manganese, iron, cobalt, nickel, copper and zinc, and are also known as the trace metals as well as fluorine, silicon, selenium, arsenic and iodine. The bulk metals form 12% of the human body-weight whereas the trace elements represent less than 0.01% [6]. Within cells, distribution of metal ions is more complex in that the cells must themselves control any competition between the metal ions in the same internal compartment; moreover, the metal ions must also have a functional value. Those elements that are found prominently in most cells, together with their free concentrations in the central cell compartment [6-8]. The concentration of these elements varied from an element to another.

Table 2. The concentration of selected elements in the human body [6,7]

Element Concentration in body

(Wt) Concentration in cytoplasm (mol/L)

Na+ 0.1 10-3 K+ 0.1 10-1 Mg2+ 0.04 10-3 Ca2+ 10-7 Mn2+ 2 x 10-5 10-7 Fe2+ 0.005 10-7 Co2+ 9 x 10-6 < 10-9 Ni2+ 2 x 10-5 < 10-9 Cu2+ (Cu+) 2 x 10-4 < 10-14 Zn2+ 0.003 10-11 MoO4-2 10-8


NUTRITIONALLY ESSENTIAL AND NON-ESSENTIAL METALS Metals can also be classified as being nutritionally essential for humans such as cobalt,

chromium (III), copper, iron (II) and iron (III), manganese and molybdenum, in addition to non-metal namely selenium and "d" closed zinc element. On the other hand metals one such as arsenic, cadmium, lead, and mercury, and their inorganic compounds can even be toxic to human health [9]. One can satte that these elements are considered as soft ones and can perform stable compounds with soft sulfur compounds such as glutathione reductase and thioproteins, preventing the last ones from preventing oxidative stress. Still there are some metals which are not essential to human health but may have some beneficial effects at low levels of exposure e.g., silicon, nickel, boron, and vanadium. These elements have the capability of forming oxygen compounds. Meanwhile, boron, nickel, silicon, and vanadium have been shown to have biological functions in plants and some animals but essentiality for humans has not been demonstrated [9].

Soft elements are characterized by high polarizability, low electronegativity, small negative charge, large size, covanent type of bond usually associated with the base (electron donor), available empty orbitals on donor atom are low lying and associative. Hard elements are characterized by low polarizability, high electronegativity, large negative charge, small size, ionic electrostatic type of bond usually associated with the base, high energy and associative available empty orbitals on donor atom.

Table 3. Nutritionally essential and non-essential elements

Nutritionally essential elements (soft and borderline elements)

Elements with possible beneficial effects (hard and borderline elements)

Elements with no known beneficial effects (soft and hard elements)

Cobalt : d block element Chromium III : d block element Copper : d block element Iron: d block element Manganese : d block element Molybdenum : d block element Zinc : d block element Selenium : b block element

Boron : s block element Vanadium : d block element Nickel : d block element Silicon : p block element

Aluminum s: block element Barium s : block element Beryllium s : block element Strontium s: block element Thallium s: block element Silver : d block element Antimony : p block element Arsenic : p block element Cadmium : p block element Lead : p block element Mercury (p)

THE BIOLOGICAL VALUES OF IRON, COPPER, MANGANESE, NIKEL, CHROMIUM, ZINC, MOLYBDENUM, COBALT AND

VANADIUM IN HUMAN Trace elements are those elements occurring in the human body but constituting 0.01% of

body weight [10]. The trace elements include iron, manganese, copper, zinc, molybdenum,


cobalt, vanadium, chromium, nickel, fluorine, silicon, selenium, arsenic and iodine. Their concentrations, however, vary in different tissues. In particular iron, copper, selenium, manganese, chromium, molybdenum and iodine are essential to human health that metalloproteins represent about one third of all structurally characterized proteins with a biological activity and over 40% of all enzymes contain metals [6, 11]. These metals are also required to maintain the brain's biochemistry. Their interchangeable prevalent ionic forms and affinity for functional groups occurring in proteins are unique properties of transition metals that make them useful in biochemical redox reactions [12, 13]. Metals determine the geometry of enzymatic active sites, act as centers for enzyme reactivity, and act as biological oxidationreduction facilitators [8]. Transition metals that exist in multiple oxidation states serve as electron carriers e.g., iron ions in cytochromes; as facilitators of oxygen transport e.g., iron ions in hemoglobin and as sites at which enzyme catalysis occurs e.g., copper ions in superoxide dismutase. Transition metal ions that exist in single oxidation states, such as zinc(II), function as structural elements in superoxide dismutase and zinc-finger motifs [8]. Proteins with which transition metals and zinc are most commonly associated catalyze the intramolecular or intermolecular rearrangement of electrons. Although the redox properties of the metals are important in many of the reactions, in others the metal appears to contribute to the structure of the active state, e.g., zinc in the Cu-Zn dismutases and some of the iron in the photosynthetic reaction center. Sometimes equivalent reactions are catalyzed by proteins with different metal centers; the metal binding sites and proteins have evolved separately for each type of metal center [7].Copper- and zinc-containing superoxide dismutase, manganese-containing superoxide dismutase, catalase, and glutathione peroxidase form the primary enzymic defense against toxic oxygen reduction metabolites. But, metal-induced uncontrolled redox reactions or displacement of endogenous metal cofactors from their cellular binding sites can also lead to cellular perturbations [12, 13]. Moreover, any of the trace elements has the potential to be toxic if given in sufficiently large quantities, but that for most trace elements normal physiological or dietary conditions are extremely unlikely to achieve such levels [14]. Whilst Fe, Cu, Cr, V and Co undergo redox-cycling reactions, for a second group of metals, Hg, Cd and Ni, the primary route for their toxicity is depletion of glutathione and bonding to sulfhydryl groups of proteins. Arsenic (As) is thought to bind directly to critical thiols, however, other mechanisms, involving formation of hydrogen peroxide under physiological conditions, have been proposed [15]. [As5+ + H2O2 OH + As3+]. Iron and copper are redox-active metals (i.e. can switch between oxidized and reduced forms: Cu2+/Cu1+ and Fe3+/ Fe2+) and often participate in electron transfer [16] (see below). Iron and copper are also involved in dioxygen (O2) storage and carriage via metalloproteins [e.g. hemoglobin, myoglobin and hemocyanin] [6]. Copper is found in essential proteins such as cytochrome c oxidase, catechol oxidase, and ascorbate oxidase, a Cu/Zn superoxide dismutase, and many other oxidoreductases, and monooxygenases. It is responsible for oxidation-reduction processes that involve electron transfer, dioxygen chemistry, and reduction of nitrogen oxides. Its position in the middle of the elements of the first transition series (so designated because their ions have incompletely filled d orbitals) implies that iron has the possibility of various oxidation states (from II to +VI), the principal ones being II (d6) and III (d5), although a number of iron-dependent monooxygenases generate high valent Fe(IV) or Fe(V) reactive intermediates during their catalytic cycle [17](Crichton, 2001). Copper exists mainly in two oxidation states, Cu(I) and Cu(II), and often changes between these two states while catalyzing reactions. Transition metals such as iron and copper are


involved in both metal-catalyzed (auto) oxidations and reactions leading to hydroxy1 radical production from superoxide, a species frequently proposed to initiate lipid peroxidation. Similar mechanisms involving the Fenton-like production of superoxide anion and hydroxyl radical appear to be involved for iron, copper, chromium, and vanadium. However, with some metal ions, such as mercury, nickel, lead, and cadmium, depletion of glutathione and protein-bound sulfhydryls may play a primary role in the overall toxic manifestations [12].

2O2-+2H+ H2O2+O2 Fe2++H2O2 Fe3+ +OH+OH- Traces of Fe3+ can react further with H2O2: Fe3++H2O2Fe2++O2-+H+ Possible more reactions: OH+H2O2H2O+H++O2- O2-+Fe3+ Fe2++O2 OH+Fe2+Fe3++OH- 2H2O2 + Fe salt catalyst2H2O+O2 Cu++ H2O2 Cu2+ +OH +OH- CH3OH+OH H2O+CH2OH Cl+OHCl+OH- H2O2+O2-O2+OH-+OH Fe3++O2-Fe2++ O2 (O2- reducing the iron salt) Fe2++ H2O2 Fe3+ +OH +OH- (Fenton reaction) Net : O2-+H2O2 + Fe salt catalyst O2+OH+OH- The levels of essential metals are strictly regulated by specific metal transporters at

gastrointestinal tract and blood-brain barrier. When dietary levels of essential metals are low, levels of the corresponding transporters increase in the intestine, after which there is a greater potential for increased transport of toxic metals. The divalent metal transporter 1 (DMT1), actively transport Fe, Zn, Mn, Co, Cd, Cu, Ni, and Pb, via a proton-coupled mechanism [18]. Involvement of intracellular transporters for copper and zinc has been shown in animal models of Alzheimer's disease, raising the possibility that higher levels of iron, zinc and copper might be due to a disruption in the activity of transporters. Accordingly, exposure to toxicants that affect the activity of transporters potentially could contribute to the aetiology/progression of neurodegenerative diseases [19] as we will see later. Two non-enzymatic proteins, ferritin and ceruloplasmin, also appear to play important roles in transition-metal storage and antioxidant defense in vivo. Ferritin, which binds iron in the cytoplasm of mammalian cells, and ceruloplasmin, which binds copper in plasma, are thought by many to contribute a significant antioxidant capacity to bodily fluids. Other proteins that


bind metals include transferrin, haptoglobin, albumin and metallothioneins are in the same sense protective. The latter belong to a family of low molecular weight, cysteine rich intracellular proteins that bind transition metals, including zinc and cadmium [20].

Iron Iron is the most abundant transition metal and the second most prevalent metal of the

earths crust [17]. Iron is essential for microbial, plant, animal, and human life [21]. The amount of total body iron is around 3 to 4 grams which is contained mainly in the haemoglobin of the erythrocytes. The major site of iron storage in the body is the liver. Red cell turnover constitutes the major pool of iron turnover in the body [22, 23]. Most iron is in the form of heme iron that is found in hemoglobin, myoglobin, and iron-containing enzymes (such as catalase and the cytochromes). More than two thirds of the bodys iron content is incorporated into hemoglobin in developing erythroid precursors and mature red cells. The rest of the total body iron exists as a nonheme iron, which consists of plasma iron, iron bound to transferrin, and stored iron in ferritin and hemosiderin [22, 24]. Iron is a key player in some of the most central processes of biological systems, including oxygen transport and utilization, electron transfer, metabolism of nucleic acids and many other key biological molecules, degradation of biological pollutants, and many other reactions [25]. The duodenum and proximal jejunum are the main sites of absorption of dietary iron. Haem iron is absorbed more efficiently than non-haem iron, apparently by endocytosis of the intact ironprotoporphyrin complex at the enterocyte brush border. Iron is then liberated from the haem moiety by the action of haem oxygenase and enters the intracellular iron pool from which it can be transferred across the basolateral membrane, bind to transferrin and enter the circulation. Meanwhile, absorption of non-haem iron requires reduction of ferric iron at the brush border membrane, followed by internalization by a proton coupled transporter [2]. In normal human plasma, serum iron (~ 20 M) exists primarily in the Fe3+ form and is complexed with the high affinity iron binding protein transferrin, an 80-kd glycoprotein that is synthesized in the liver (Tf; ~ 40 M) in a 2:1 ratio. At blood pH (7.4), each molecule of transferrin can bind two atoms of ferric iron [27]. Only one third of the transferrin is saturated with iron which implies that all the iron in the circulation is bound to transferring. In circumstances in which the binding capacity of transferring becomes saturated, as for example in iron loading disorders, iron forms low-molecular-weight complexes, the most abundant of which is iron citrate [26]. Most cellular uptake of ferric iron (Fe3+) occurs via receptor-mediated endocytosis of transferrin (vesicular import pathway IN2) which binds to specific membrane-bound transferrin receptor (TfR). Inside the cell, members of the Steap family of ferric reductases localize to the endosome and reduce Fe3+ (ferric) to its Fe2+ (ferrous) form before Fe2+ is released into the cytosol by the divalent metal transporter-1 (DMT1) in an H+-dependent manner [28]. DMT1 is not specific to iron; it can transport a wide variety of divalent metal ions, including manganese, cobalt, copper, zinc, cadmium, and lead [22]. Free Fe2+ in the cytosol constitutes a labile iron pool (~ 2-3 M) for cellular utilization, supplying Fe2+ molecules as co-factors for many Fe2+-dependent enzymes in the cytosol, mitochondria, and nucleus. If cytosolic iron is not immediately used, it can also be rapidly sequestered by cytosolic Ft into a non-reactive Fe3+- Ft complexes. Iron can be


released from cells by the iron exporter ferroportin [29]. Fe3+ can be bound in the extracellular space by Tf, citrate, ascorbate, or ATP. Cytosolic or intralysosomal iron overload may catalyze the production of free radical oxides via the Fenton reaction. Radical oxides may cause cellular damage by oxidizing macromoleucles such as lipids, DNA, and proteins. Iron transport across the blood brain barrier is the result of receptor-mediated endocytosis of iron-containing transferrin by capillary endothelial cells, followed by recycling of transferrin to the blood and transport of non-transferrin-bound iron into the brain. The principle sources of extracellular transferrin in the brain are hepatocytes, oligodendrocytes, and the choroid plexus [30].

Copper Copper is the third most abundant metallic element in the human body, following iron

and zinc, and it is important in all other life forms. The daily intake of Cu ranges from 0.6 to 1.6 mg / day with the main sources of Cu being seeds, grains, nuts, beans, shellfish, and liver. It is estimated that the adult human body contains between 50-150 mg [31, 32]. Free Cu2+ content of human plasma is approximately 2x10-16 M [33-36] and total copper concentrations in most tissues are approximately 5x10-5 M total copper [37]. Clinically apparent copper deficiency is extremely rare and difficult to achieve by dietary means, but loss-of-function mutations in the ATP7A gene encoding a copper-transporting P1B-type Atpase, involved in the delivery of copper to the secreted copper enzymes and required for copper absorption and homeostasis is associated with Menkes disease, resulting severe tissue copper deficiency, seizures, neurodegeneration, psychomotor deterioration, failure to thrive, and death in early infancy [38, 39]. On the other hand, the toxicity associated with excess copper manifest in Wilson disease, a rare, autosomal recessive disorder of copper metabolism where tissue copper accumulation results in hepatic, neurologic, or psychiatric disturbances. Mutations in the ATP7B gene which is located on the long arm (q) of chromosome 13 (13q14.3) cause failure of copper excretion into the bile and a defective incorporation of copper into ceruloplasmin [40]. Copper homeostasis is maintained by adjusting intestinal copper absorption and copper excretion in bile. Copper is absorbed in the proximal intestinal tract, facilitated by the simultaneous absorption of amino acids and decreased by zinc and vitamin C. Excretion which occurs primarily through the bile is increased by molybdenum, as well as by diets high in calcium and phosphorus. The excretion of copper into the gastrointestinal tract increases when dietary copper is high and more is absorbed, thereby, protecting against excess accumulation of copper in the body. Vice versa, low copper intake is associated with little endogenous copper is excreted, protecting against copper depletion [41]. This is controlled by specific transporters that take up metals at the apical surface and export them at the basolateral surface of intestinal cells, and are involved in their intracellular distribution. The level of these transporters increases or decreases in the intestine according to the dietary levels of essential metals [19]. The uptake of Cu into the cells is mediated by two transporter proteins; Cu transporter 1 (Ctr1) and divalent metal transporter 1 (DMT1) that transports Cu across the plasma membrane (located on the plasma membrane). ATP7A and ATP7B are membrane-bound copper-transporting P-type ATPases that catalyze an ATP-dependent transfer of Cu to intracellular compartments or participate in


Cu efflux from the cell [42]. Cellular copper excretion also involves COMMD1 [copper metabolism (Murr1) domain containing 1] [43]. Most of Cu ions absorbed from the small intestine are distributed to liver and kidneys; they are transported in blood mostly (65-90%) by tightly binding to protein "ceruloplasmin", synthesized in the liver where it binds Cu and the rest of Cu loosely binds with albumin, transcuprein and amino acids (e.g., histidine) [33]. Only reduced Cu can be transported [43]. Cu is transported into the brain through the blood brain barrier as a free Cu ion [44]. Redox cycling between Cu2+ and Cu1+ can catalyse the production of highly toxic hydroxyl radicals, with subsequent damage to lipids, proteins, DNA and other biomolecules. Free intracellular copper is detoxified primarily by metallothionein (MT) proteins. Metallothioneins are ubiquitous low molecular weight proteins rich in cysteine residues that have high metal-binding capacities. They bind heavy metal ions (mainly Cd, Zn and Cu) via metal-thiolate clusters, thus they are essential in metal homeostasis and protect against metal toxicity [45, 46]. The incorporation of intracellular copper into the structure of different cuproenzymes is carried out by copper chaperones; Atox1 (delivers copper to copper transporting ATPases in the late Golgi), CCS (copper chaperone for SOD, required for copper incorporation into Cu/Zn superoxide dismutase), and Cox17, Sco1 and Sco2 (delivers copper to subunits of mitochondrial cytochrome c oxidase) [43, 47]. Copper chaperones through transporting copper in the cytoplasm to the site of utilization by copper-dependent proteins, ensure that copper can reach its specific target protein and also prevent inappropriate copper interactions with other cellular, protecting the cell from the deleterious effects of free copper e.g., protection against oxidative stress [48]. An increase in the endogenous level of Atox1 expression have been demonstrated protect neurons against oxidative stress. Furthermore, overexpression of an Atox1 metal binding mutant is detrimental to cell viability. Furthermore, mutations in the copper binding motif of Atox1 result in a dominant negative phenotype where the cell viability is diminished [49]. The copper chaperone for the superoxide dismutase gene is necessary for expression of an active, copper-bound form of superoxide dismutase in vivo in spite of the high affinity of superoxide dismutase for copper. This metallochaperone protein activates the target enzyme through direct insertion of the copper cofactor and apparently functions to protect the metal ion from binding to intracellular copper scavengers. Thus intracellular [Cu]free is limited to less than one free copper ion per cell and a pool of free copper ions is not used in physiological activation of metalloenzymes [50]. The highest concentration of CCS is found in the kidney and liver. There is also a significant amount of this copper chaperone protein in the CNS being found throughout the neuropil, with expression largely confined to neurons and some astrocytes [51]. Cu is required as a catalytic cofactor in various cuproenzymes, including the mitochondrial cytochrome c oxidase, a component of the electron transport chain, caeruloplasmin, monoamine oxidase, dopamine B-hydroxylase, tyrosinase, involved in the production of melanin histaminase, lysyl oxidase, involved in the cross-linking of elastin and collagen, and Cu/Zn-superoxide dismutase. The enzyme superoxide dismutase (SOD) occurs in three forms in mammalian systems: (1) CuZnSOD (SOD1) found in the cytosol, (2) MnSOD (SOD2) found in mitochondria, and (3) CuZnSOD found in extracellular space (SOD3). The active site in Cn/Zn superoxide dismutase consists of one Cu atom and one Zn atom, coordinated to a common histidine ligand; His63 in human SOD1 and His61 in human SOD2. The copper atom is coordinated by three other histidine residues and zinc is coordinated by two other histidine residues and one asparagines [52]. Additionally, many


bacterial SOD enzymes contain iron. Copper is also an essential component of chromatin and is involved in chromatin scaffold proteins. Food copper (organic copper) is processed by the liver and is transported and sequestered in a safe manner. Inorganic copper, such as that in drinking water and copper supplements, largely bypasses the liver and enters the free copper pool of the blood directly. This copper is potentially toxic because it may penetrate the blood/brain barrier [53]. Cu toxicity comes about from its ability to produce reactive oxygen species, displace other metal ions, peroxidize lipids, and directly cleave DNA and RNA. Copper exists physiologically in two redox states, as cuprous Cu1+ (reduced) or cupric Cu2+ (oxidized) and can interchange between these forms by accepting or donating an electron. This allows the cation to participate in biochemical reactions as a reducing or oxidizing agent [54]. This same properties which make copper being essential for various enzymatic reactions, is also responsible for copper toxicity via its ability to generate free radicals, in particular, the highly reactive hydroxyl radical through Fenton chemistry, which subsequently can damage lipids, proteins, DNA and other biomolecules [55]. Most extracellular copper is Cu(II) and most, if not all, intracellular copper is Cu(I). Typical intracellular copper-binding proteins, such as the Cu-transporting P-type ATPases ATP7B and ATP7A bind copper as Cu(I)[54]. It has been suggested that, the toxic and carcinogenic potential of mineral dusts inhaled into the lungs is related, in part, to biochemical reaction mechanisms involving iron and reactive oxygen species that occur at the mineral surface [56, 57]. Many cancer tissues contain highly elevated levels of Cu [58, 59]. The reasons for this elevation are unclear but one possible result is increased angiogenesis [60, 61]. The copper-chelating agent, trientine, suppressed tumor development and angiogenesis in the murine hepatocellular carcinoma cells [62]. A copper transporter, Ctr1p, was discovered to mediate cisplatin uptake in yeast and mammals. Increased cisplatin resistance caused by deletion of the Ctr1 gene suggests its important role in cellular resistance. This finding presents a potential target for modulating cisplatin antitumor efficacy [63].The combined treatment with a copper chelator and cisplatin increased cisplatin-DNA adduct levels in cancerous but not in normal tissues, impaired angiogenesis, and improved therapeutic efficacy. Others reported increased accumulation of iron, nickel, chromium, zinc, cadmium, mercury, and lead in breast cancer samples [64]. Cancerous cells have more transferrin receptors than normal cells [65] because of their need for oxygen. In our opinion, the high levels of singlet oxygen attacks the species of sulphur (glutathione) which acts as an antioxidant. The complexation of metals with SH bearing compounds leads to a decrease in antioxidant capacity.

Manganese Manganese (Mn) is the 12th most abundant element in the earths crust comprising about

0.1% of the earths crust [66, 67]. Manganese is an essential mineral for humans, animals, and plants. It is present in virtually all diets at low concentrations. Mn is present in most tissues of all living organisms and is present naturally in rocks, soil, water, and food. Humans maintain stable tissue levels of Mn via tight homeostatic control of both absorption and excretion of ingested Mn and limit tissue uptake at low to moderate levels of inhalation exposure [68-70]. The most significant source of manganese exposure for the general population is food. The highest manganese concentrations are found in nuts (up to 47 g/g) and grains (up to 41 g/g). Lower levels are found in milk products (0.020.49 g/g), meat, poultry, fish, and eggs


(0.103.99 g/g), and fruits (0.2010.38g/g). Tea and leafy green vegetables have also been found to be dietary sources of manganese [71]. Mn is absorbed from the gastrointestinal tract, within the plasma, Mn is largely bound to gamma-globulin and albumin, and a small fraction of trivalent (3+)Mn is bound to the iron-carrying protein, transferring [70]. The Mn adequate intake for adult men and women is 2.3 and 1.8 mg/day, respectively [71]. Serum concentration of Mn in healthy subjects is about 0.050.12 g/dl [72].

The total amount of manganese in the adult human (70 kg) has been determined to be about 10-20 mg, most of which is found in skeleton, liver, kidney, pancreas and the heart. The rest is distributed widely throughout all the tissues and fluids. A daily requirement for manganese has not been established; however, it appears that a minimum intake of 2.5 to 7 milligrams per day meets human needs. In humans, manganese is an essential nutrient that plays a role in bone mineralization, protein and energy metabolism, metabolic regulation, cellular protection from damaging free radical species, and the formation of glycosaminoglycans. An adequate amount of this trace mineral would be absolutely vital during gestation for normal foetal growth and development [73,74]. Mn dependent enzyme families include oxidoreductases, transferases, hydrolases, lyases, isomerases, and ligases. Manganese metalloenzymes include arginase (liver urea), glutamine synthetase (brain ammonia metabolism), phosphoenolpyruvate decarboxylase (gluconeogenesis). Mn is also the key component of superoxide dismutase (Mn-SOD) found in mitochondria of the cells. The manganese-containing superoxide dismutase (MnSOD) is a major component of the cellular defence mechanisms against the toxic effects of the superoxide radical [75].

While Mn deficiency is extremely rare in humans, toxicity due to overexposure of Mn is more prevalent. Mn toxicity has been reported in individuals exposed to high environmental levels of Mn e.g. miners, welders and those living near ferroalloy processing plants. Toxicity can also result from dietary overexposure and is evidenced primarily in the central nervous system, although lung, cardiac, liver, reproductive and fetal toxicity have been noted [72]. The brain appears to be especially vulnerable to Mn accumulation resulting in is an established clinical entity, referred to as manganism which is a progressive disorder of the extrapyramidal system similar to Parkinson's disease in its clinical features, both in laboratory animals and humans [69, 70]. Neurotoxicity due to excessive brain manganese (Mn) accumulation can occur via occupational exposure to aerosols or dusts that contain extremely high levels (>1-5 mg Mn/m(3)) of Mn, consumption of contaminated well water, or parenteral nutrition therapy in patients with liver disease or immature hepatic functioning such as the neonate(decreased biliary excretion). Although Mn exposure via parenteral nutrition is uncommon in adults, in premature infants, it is more prevalent [76].

Transport of manganese across the blood-brain barrier occurs by means of a series of transporters. Movement can take place by facilitated diffusion, active transport [77] via divalent metal transport and transferring (Tf)-dependent transport. Biliary excretion represents the main mechanism by which manganese is eliminated from the body [78]. Mn disposition in vivo is influenced by dietary iron intake and stores within the body since the two metals compete for the same binding protein in serum (transferrin) and subsequent transport systems (divalent metal transporter, DMT1). There appear to be two distinct carrier-mediated transport systems for Mn and ferrous ion: a transferrin-dependent and a transferrin-independent pathway, both of which utilize DMT1 as the transport protein [79]. In primary astrocyte cultures derived from neonatal rats.. Both iron deprivation (ID) and iron overload (+Fe) caused significant increases (p


TfR associated with +Fe treatment and the increased DMT-1 levels suggest that DMT-1 is a likely putative transporter of Mn in astrocytes [80]. Fe deficiency can enhance brain Mn accumulation even in the absence of excess Mn in the environment or the diet, suggesting that there is homeostatic relationship among several essential metals in the brain and not simply between Fe and Mn [81]. Mn transport appears to be temperature, energy, and pH dependent, but not Fe or Na(+) dependent. These data suggest that Mn transport across the BBB is an active process [82]. After intravenous contrast injection, normal (enteral) regulation mechanisms for manganese homeostasis are bypassed, and there is a danger of individual overdosing. Excess manganese, for example in patients with chronic liver disease or with chronic parenteral nutrition, has already been detected by magnetic resonance imaging in the basal ganglia and was found to coincide with neurologic symptoms [83].

Zinc Zn is the trace element which is essential for cell growth and maintenance of cellular

integrity. It is an integral structural component of nearly 300 enzymes and other proteins involved in the expression of genetic information and cellular signal transduction. Zinc is present in all body tissues and fluids. The total body zinc content has been estimated to be 30mmol (2g). Skeletal muscle accounts for approximately 60% of the total body content and bone mass, with a zinc concentration of 1.53mol/g (100200g/g), for approximately 30%. Lean red meat, whole-grain cereals, pulses, and legumes provide the highest concentrations of zinc: concentrations in such foods are generally in the range of 2550mg/kg (380760mol/kg) raw weight. Fish, roots and tubers, green leafy vegetables, and fruits are only modest sources of zinc, having concentrations


Zinc plays specific and important catalytic, co-catalytic and structural roles in enzyme molecules and in many other proteins and biomembranes. A well-known example of the structural role of zinc in cellular and subcellular metabolism is the zinc finger motif, ubiquitous in transcription proteins. The configuration of zinc fingers, critical to DNA binding, is determined by the single zinc atom at their base. The linking of zinc fingers to corresponding sites on the DNA initiates the transcription process and gene expression. Motifs similar to zinc fingers have been identified in nuclear hormonal receptors including those for vitamin D, estrogen and testosterone. Zinc plays an important role as ionic signaling in large number of cells and tissues. Zinc-binding proteins account for nearly half of the transcription regulatory proteins in the human genome, and during the past two decades, well over 2000 zinc-dependent transcription factors involved in gene expressions of various proteins have been reported [87, 88].

Among the transition metals playing key roles in biological systems, zinc is second only to iron in biological prevalence. Unlike iron and copper, zinc has only one oxidation state accessible under physiological conditions, and therefore does not participate in catalysis of redox chemistry or electron transfer reactions. Unlike other first-row transition metals (e.g., Sc2+, Ti2+, V2+, Cr2+, Mn2+, Fe2+, Co2+, Ni2+ and Cu2+), the zinc ion (Zn2+) contains a filled d orbital (d10) and therefore does not participate in redox reactions but rather functions as a Lewis acid to accept a pair of electrons [89]. The types of enzymatic reactions in which zinc is found to play a role include peptidases and amidases, phosphatases, phospholipase, phosphotriesterase, deaminases and alcohol dehydrogenase, among others. One mechanism by which zinc is believed to facilitate some of these reactions is through binding and thereby lowering the pKa of water, generating a localized high concentration of metal-bound hydroxide in the active site, which can act as a nucleophile in the hydrolytic reactions [25].

Zinc is very different from magnesium, manganese and calcium. It binds nitrogen and sulfur much more readily and also shows lower coordination numbers in spite of its size (which is intermediate between that of magnesium and divalent manganese. It was found that the predominant ligand to zinc depends on the coordination number of the metal ion, whereas the other metal ions just listed each prefer oxygen at all coordination numbers. Zinc tends to form 4-, 5-, and 6- coordinate complexes with about equal ease. When the coordination number is four, sulfur is as likely a ligand as oxygen, when it is 5 nitrogen is the most common ligand, and for coordination numbers 6 and 7 oxygen predominates as a ligand. Thus, zinc can possibly replace magnesium or divalent manganese (since they both bind oxygen when their coordination number is 6), but it has other options for coordination, in keeping with its reactivity in the active sites of enzymes (often involving a change in coordination number). [90].

Molybdenum Molybdenum is a very rare element with a crustal abundance of about 1.2 mg/kg [91].

Molybdenum is the only second-row transition metal that is required by most living organisms [92]. The tolerable upper intake level for the United States and Canada was set at 2 mg/d in 2002 [93], and the European Commission suggested an upper limit of 0.6 mg/d [94].The availability of molybdenum to biological systems is due to the high water solubility of oxidized forms of the metal. In man, absorption of molybdenum after oral intake is in the


range of 28-77% and urinary excretion is 17-80% of the total dose [95]. Stable-isotope studies of molybdenum metabolism have been conducted in which molybdenum was added to the diet and was assumed to be absorbed and utilized similarly to the molybdenum in foods. These studies showed that molybdenum is well absorbed over a range of intakes, that it is rapidly excreted via the urine, and that total body molybdenum retention is regulated primarily via urinary excretion. With high molybdenum intake, molybdenum absorption increases and excretion is more rapid [96]. In healthy young men, absorption of molybdenum from the intestine increased at higher molybdenum intakes.Urinary output appears to be the key pathway for regulating the body's exposure to molybdenum. Higher molybdenum intake resulted in higher rates of urinary excretion [97]. Because molybdenum toxicity is associated with copper intake or depleted copper stores in the body, humans who have an inadequate intake of dietary copper or some dysfunction in their copper metabolism that makes them copper-deficient could be at greater risk of molybdenum toxicity [95].

Deficiency is rare in humans and is limited primarily to genetic defects leading to serious abnormalities. Molybdenum cofactor deficiency in humans results in the loss of the activity of molybdoenzymes sulfite oxidase, xanthine dehydrogenase, and aldehyde oxidase. The resultant severe phenotype, which includes progressive neurological damage leading in most cases to early childhood death, results primarily from the deficiency of sulfite oxidase. Molybdenum cofactor deficiency and isolated sulfite oxidase deficiency are autosomal recessive inborn errors of metabolism with severe neurological symptoms resulting from a lack of sulfite oxidase activity [98, 99].

The metal itself is biologically inactive unless it is complexed by a special cofactor. With the exception of bacterial nitrogenase, where Mo is a constituent of the FeMo-cofactor, Mo is bound to a pterin, thus forming the molybdenum cofactor (Moco) which is the active compound at the catalytic site of all other Mo-enzymes. Several enzymes in humans contain molybdenum catalysing diverse redox reactions. In man, these enzymes, sulfite oxidase, xanthine oxidase, and aldehyde oxidase, contain the same molybdenum complex, molybdopterine. The molybdenum enzymes xanthine oxidase, sulfite oxidase and aldehyde oxidase are involved in the human diseases of gout, combined oxidase deficiency and radical damage following cardiac failure. Sulfite oxidase catalyzes the final step in the degradation of sulfur-containing amino acids and is involved in detoxifying excess sulfite. Xanthine oxidase is the final enzyme in the conversion of hypoxanthine to xanthine, and subsequently, to uric acid. Aldehyde oxidase catalyzes the oxidation of aldehydes, pynmidines, purines, pteridines, and related compounds [100, 101].


The metal is found in three different oxidation states (IV, V and VI) and has the desirable

ability to couple biological compounds that are obligatory two-electron carriers (e.g. NADH) with obligatory one-electron carriers (e.g. iron-sulphur centres and cytochromes) [102].

Cobalt Cobalt is the least abundant 3dr transition metal (in sea water and earth crust). Cobalt is

found in vitamin B12 , its only apparent biological site. Vitamin B12 occurs in the body mainly as methylcobalamin, adenosylcobalamin and hydroxycobalamine(a precursor to methyl and adenosylcobalamine). Hydroxycobalamine is most stable form of all cobalamine and is water soluble. B 12 is found in animal protein and not in vegetables. Cobalt is an essential metal for humans and has to be ingested in the form of cobalamines (vitamin B12). Only microorganisms can biosynthesize cobalamine. Cobalt in cobalamines can be reduced and oxidized (2-one electron steps), thus cobalamine containing enzymes participate in redox reactions. Vitamin-B 12 deficiency causes the severe disease of pernicious anemia in humans, which indicates the critical role of cobalt [103, 104].

The vitamin B12 cofactors coenzyme B12 or 5-deoxy-5-adenosylcobalamin (AdoCbl), and methylcobalamin (MeCbl) consist of cobalt(III) bound to a substituted corrin ring and an alkyl group (either adenosyl or methyl). Adenosylcobalamin (AdoCbl) or coenzyme B12 is an organometallic cofactor that functions as a radical reservoir and is used by enzymes to catalyze rearrangement reactions in which a hydrogen atom and a variable group on adjacent carbons are interchanged (mutases and eliminases). Methylcobalamin (MeCbl) is the cofactor of several methyltransferases, such as methionine synthase (MetH), which catalyzes methionine biosynthesis both in mammals and bacteria [104, 105].

Chromium Chromium is an essential nutrient required for sugar and fat metabolism. The estimated

safe and adequate daily dietary intake for Cr is 50 to 200 microg. However, most diets contain less than 60% of the minimum suggested intake of 50 microg, suggesting that the normal


dietary intake of Cr for humans is suboptimal. Trivalent Cr has a very large safety range and there have been no documented signs of Cr toxicity in any of the nutritional studies at levels up to 1 mg per day [106]. Trivalent chromium is an essential nutrient required for sugar and fat metabolism. Most recent evidence strongly supports the conclusion that there is little fear of toxic reactions from chromium consumption. In addition to type 2 diabetes mellitus, chromium supplementation may be useful to direct overall weight decrements specifically towards fat loss with the retention of lean body mass and to ameliorate many manifestations of aging [107]. There is growing evidence that chromium may facilitate insulin signaling and chromium supplementation therefore may improve systemic insulin sensitivity. However, supplementation with chromium picolinate, a stable and highly bioavailable form of chromium, has been shown to reduce insulin resistance and to help reduce the risk of cardiovascular disease and type 2 diabetes [108]. However, controversy exists as to whether dietary supplementation with chromium should be routinely recommended in subjects without documented deficiencies [109]. Whether chromium is an essential element has been examined for the first time in carefully controlled metal-free conditions using a series of purified diets containing various chromium contents. Animal studies reveal that a diet with as little chromium as reasonably possible had no effect on body composition, glucose metabolism, or insulin sensitivity compared with a chromium-"sufficient" diet [110].

Vanadium Vanadium, a dietary micronutrient, is yet to be established as an essential part of the

human diet. Vanadium is abundant in rocks and soil [110]. Constituting 0.015% of earth's crust, vanadium is about as abundant as zinc [111]. In water the presence of vanadium derives almost exclusively from the solubilization of the metal present in soil and in rocks [110]. Exposure to the vanadium in water is enough to affects its presence in the daily diet and determines greater values of the element in the principal biological liquids in people [112]. The metal is present in comparatively high concentration of vanadium in sea water, being second most abundant transition metal (30 nM Na +2VO-4), only surpassed by molybdenum (100 nM molybdate), and clearly more abundant than iron (0.021 nM). Vent-derived iron oxides have been shown to scavenge vanadium from sea water and thus to contribute in controlling the concentration and cycling of vanadium in the oceans [111]. Concentrations in soil vary in the range 3-310 g/g and may reach high values (up to 400 g/g) in areas polluted by fly ash. The concentration of vanadium in water is largely dependent on geographical location and ranges from 0.2 to more than 100 g/litre in freshwater, and from 0.2 to 29 g/litre in seawater [113]. Vanadium is introduced into man through the intake of food, especially whole meal cereals, but also beef, chicken, milk, spinach, mushrooms, parsley [114]. The mean vanadium concentration in the diet was reported to be 32 g/kg (range 19-50 g) and the mean daily intake was estimated to be 20 g/day [113]. Absorbed vanadium is transported mainly in the plasma, bound to transferrin. Pentavalent vanadium is reduced in erythrocytes to the tetravalent form. This reduction is a glutathione-dependent process [113]. It appears that values, around 1 nmol/l for blood and serum and around 10 nmol/l or slightly lower for urine may be considered tentative normal values [115].

This transition element is known to influence a battery of enzymatic systems, namely phosphatases, ATPases, peroxidases, ribonucleases, protein kinases and oxidoreductases.


In biological conditions, vanadium fulfils two conditions for a potential biometal: (i) redox activity in an electrochemical potential (and free energy) frame relevant for biochemical processes, and (ii) susceptibility for nucleophilic substrates.Vanadium easily switches between the oxidation states V and IV (which, along with III, are the oxidation states of naturally occurring vanadium compounds). The redox potential at pH 7 for the couple H2VO4-+4H+ +e- VO2+ + 3H2O amounts to -0.341 V and thus is in the range where vanadyl (VO2+) is oxidised to vanadate under aerobic conditions, and vanadate reduced to vanadyl by cellular components such as cysteine containing peptides (glutathione) and proteins, ascorbate, NADH, and phenolic compounds. The main species present under physiological aerobic conditions is the acid-base pair H2VO4- HVO42-+ H+ (pka = 8.1) [111].

Nickel Nickel is widely distributed in the environment. Natural sources of atmospheric nickel

include dusts from volcanic emissions and the weathering of rocks and soils. Thus, humans are constantly exposed to this ubiquitous element although in variable amounts. The daily dietary intake of nickel is 2535 g, and it is more than triple the daily requirement [116]. Generally, greater than 250 g nickel of Ni/g of diet are required to produce signs of Ni toxicity such as depressed growth and anaemia in animals [117]. Ni-dependent enzymes are urease, [NiFe] hydrogenase, [Ni] superoxide dismutase, CO dehydrogenase, and S-methyl-CoM reductase, which catalyzes the terminal step in methane production by methanogenic bacteria. All the Ni-proteins known to date are from plants or bacteria [116].

TRANSITION METALS AND HUMAN DISEASE

Role of Transition Elements in Cancer Cancer is undoubtly one of the most grave human disease known so far. Several

transition metals, including chromium(vi), nickel, and cadmium have been suggested as human carcinogens [118]. All these elements are soft and borderline elements i.e., they are able to associate with thiols or compounds containing SH group. Metals are widely distributed elements, usually occurring at low levels in the earths crust, although some geographic areas have naturally high levels in soil. Metals are released into the environment during mining operations, industrial and manufacturing processes, and as by-products of combustion. Metals are generally present at low concentrations in ambient air, although much higher concentrations have been measured near metal processing facilities. Metals typically do not require bioactivation, at least not in the sense that an organic molecule undergoes enzymatic modification that produces a reactive chemical species [119]. Cadmium, lead, and nickel compounds have been shown to be mutagenic and carcinogenic in rodent studies [120] because of their ability to inhibit the repair of damaged DNA. In addition, they can enhance the mutagenicity and carcinogenecity of directly-acting genotoxic agents [121].


A case-control study of breast cancer and metal exposure found an increased risk for women exposed to a group of metals (chromium, arsenic, beryllium, and nickel), as well as exposure to lead and cadmium individually [122]. A highly significant accumulation of iron, nickel, chromium, zinc, cadmium, mercury, and lead was found in the cancer samples when compared to the control group [63]. Increased Cu concentrations were also found in human lung cancer biopsies [123] and in other tumors [124]. Excessive lipid peroxidation induced malondialdehyde-DNA adducts was detected in the breast tissue of women with breast cancer leading to endogenous DNA modifications [125].

The most common airborne exposures to nickel compounds are to insoluble nickel compounds such as elemental nickel, nickel sulfide, and the nickel oxides from dusts and fumes. Contributions to nickel in the ambient air are made by combustion of fossil fuels, nickel plating, and other metallurgical processes. The most common oxidation state of nickel is the divalent (Ni2+) form [126]. Nickel is also used in electroplating baths, batteries, textile dyes, and catalysts. Ni (II) in the presence of H2O2 produced greater base damage to the DNA in chromatin than to isolated DNA, unlike Co (II) [127]. Nickel compounds are carcinogenic to humans and metallic nickel is possibly carcinogenic to humans. A 2-year inhalation study of nickel oxide in rats and mice conducted by the National Toxicology Program [128] indicated a carcinogenic effect of nickel oxide in the lungs. Occupational exposure to nickel producing anelevated risk of nasal cancer and a 30% excess of lung cancer in the workforce nasal cancer and a 30% excess of lung cancer [129]. It has been shown that histone demethylase JMJD1A and DNA repair enzyme ABH2 family of dioxygenases is highly sensitive to inhibition by nickel ions through by replacing the ferrous iron in the catalytic centers. Inhibition of these dioxygenases by nickel is likely to have widespread impacts on cells (e.g. impaired epigenetic programs and DNA repair) and may eventually lead to cancer development [130].

The U.S. National Toxicology Program (NTP, 2002)[131] carcinogenicity study of inhaled V(2)O(5) in rats and mice, concluded that clear evidence of lung tumors was seen in mice of both genders and that there was some evidence of carcinogenicity in male rats. In response to this study, vanadium pentoxide (V(2)O(5)) and other inorganic vanadium compounds have recently been evaluated by several occupational exposure limit setting committees and expert groups. It has been argued that, because of inherent weaknesses in design and procedure, the U.S. National Toxicology Program study of the carcinogenicity of inhaled vanadium pentoxide does not provide adequate evidence to support the classification by regulatory authorities of vanadium pentoxide as a Group 2B (possible) human carcinogen [132, 133]. The lungs are a significant site of entry of vanadium in the case of community exposure [113]. Vanadate enters cells where it is reduced by glutathione and other agents to vanadyl species (VO2+) and stabilized as such by various ligands. Vanadyl binds readily to proteins, amino acids, nucleic acids, phosphates, phospholipids, glutathione, citrate, oxalate, lactate, ascorbate, edetate, etc. [134]. Welding fumes contain many different metals including vanadium typically present as particulates containing vanadium pentoxide (V2O5). Recently, inhalative exposure to vanadium pentoxide in workers from a V(2)O(5) factory has been reported to cause oxidation of DNA bases, affect DNA repair, and induce formation of nucleoplasmic bridges and nuclear buds in leukocytes, suggesting that the workers are at increased risk for cancer and other diseases that are related to DNA instability [135]. In vitro, human peripheral lymphocyte cultures were exposed to 1, 2, 4, or 8 microg/mL of


vanadium(III) trioxide, vanadium(IV) tetraoxide, or vanadium(V) pentoxide (V(2)O(3), V(2)O(4), or V(2)O(5), respectively. These cultures were then screened for structural chromosomal aberrations, and mitotic index (MI) measurements were made. Cytogenetic evaluations showed that only V(2)O(4) increased the percentage of aberrant cells (without gaps) and chromosome damage (including and excluding gaps), while all compounds led to a decrease in the MI. These results demonstrate that vanadium(III), vanadium(IV), and vanadium(V) are all capable of inducing cytotoxicity, but only oxidation state IV induces clastogenic effects [136]. Furthermore, vanadium pentoxide induced pulmonary inflammation and tumor promotion in some strains of mice [137]. Vanadate generates the hydroxyl radical via a Fenton-like reaction rather than a Haber-Weiss reaction [138].

V(V)+O2- V(V)+ O2 V(V)+ H2O2 V(V) +OH+OH- Some essential metals e.g., chromium VI and iron can also be carcinogenic. Chromium is

naturally occurring in rocks, animals, plants, soil and in volcanic dust and gases. Trivalent chromium (III) is an essential nutrient for the body. Hexavalent chromium (VI), is generally produced by industrial processes. Non-occupational exposure to Cr(VI)compounds occurs from cigarette smoke, automobile emissions, areas of landfills and hazardous waste disposal sites [139, 140]. Cr(VI) compounds have been classified as group I human carcinogens by the International Agency of Research in Cancer in 1990 [141]. When inhaled, chromate particles dissolve to form soluble Cr(VI) oxyanions that enter cells through non-specific anionic transporters and are metabolically reduced within the cell by ascorbic acid and low molecular weight thiols glutathione and cysteine to their lower oxidation states such as Cr(V), Cr(IV) and Cr(III) ), the most stable form of Cr in cells. During the one-electron reduction of Cr(VI), superoxide anion (O2) and hydroxyl radicals are produced causing DNA damage [142,-146]. Reactive oxygen species were produced by the decomposition of Cr(V)(O2)4 -3 ion, resulting in DNA damage. The generation of hydroxyl radical was detected by ESR [147]. Cr(III) forms coordinate covalent and ionic interactions with DNA bases and the phosphodiester backbone, respectively [148, 149].

Cr()+O2- Cr()+ O2 Cr()+ H2O2 Cr() +OH+OH- Cr(V)+O2- Cr(V)+ O2 Cr(V)+ H2O2 Cr(V) +OH+OH- Hypervalent Cr species (Cr(V), Cr(IV)), and carbon based and oxygen radicals may also

react with DNA following Cr(VI) reduction [147, 150]. During Cr(VI) reduction, a diverse range of genetic lesions are generated including Cr-DNA binary (mono) adducts, Cr-DNA ternary adducts, DNA-strand breaks, DNA-protein crosslinks, oxidized bases, abasic sites, and DNA inter- and intrastrand crosslinks. The damage induced by Cr(VI) can lead to


dysfunctional DNA replication and transcription, aberrant cell cycle checkpoints, dysregulated DNA repair mechanisms, microsatelite instability, inflammatory responses, and the disruption of key regulatory gene networks responsible for the balance of cell survival and cell death, which may all play an important role in Cr(VI) carcinogenesis [151, 152]. Electron spin resonance (ESR) and fluorescence analysis revealed that Cr(VI) increased intracellular levels of reactive oxygen species (ROS) such as hydrogen peroxide and superoxide anion radical in dose-dependent manner [153]. Mitochondrial ROS, specifically superoxide anion (O2), mediates Cr(VI)-induced apoptosis of human lung epithelial H460 cells [154]. Cr(VI) induced a mitochondrial-mediated and caspase-dependent apoptosis in skin epidermal cells through reactive oxygen species-mediated activation of p53 [153]. Evidence indicates that trivalent chromium compounds do not cause cancer, although high concentrations in some in vitro systems have shown genetic toxicity. Hexavalent chromium compounds cause cancer in humans, in experimental animals and exert genetic toxicity in bacteria and in mammalian cells in vitro. Epidemiological evidence and animal studies indicate that the slightly soluble hexavalent salts are the most potent carcinogens [155]. In their study, Gibb et al.[156] demonstrated a strong dose-response relationship of cumulative hexavalent chromium exposure and the risk for lung cancer in exposed human workers; cumulative trivalent chromium exposure was not. The excess risk of lung cancer associated with cumulative hexavalent chromium exposure was not confounded by smoking status.

Several epidemiological studies have reported a possible correlation between measures of iron status and cancer among people in the general population and it is possible that iron accumulation in the liver is a risk factor for hepatocellular carcinoma in patients with haemochromatosis who also had increased incidence of extrahepatic cancer as well [157-159]. In this disease status in which Fe++ accumulates in tissues as a result of an autosomal recessive genetic disease leading to enhanced gastrointestinal absorption of iron that leads to a progressive increase of iron stores, the concentration of this redoxactive transition metal capable of catalyzing and/or generating free radicals like superoxide, hydrogen peroxide, and hydroxyl radical is markedly increased inducing cellular lipid peroxidation and DNA-attack [160, 161]. Studies have shown a greater ability than normal cells for tumor cells to grow and survive in the presence of high concentrations of iron [162]. In contrast, tumor growth in iron-deficient mice [163]. Iron may also act as a promoter of already initiated hepatocytes in the development of liver cancer in the rat [164]. A study of a national cohort of United States adults suggested an increased risk of dying from cancer with higher levels of serum iron, transferrin, and serum copper at baseline in males and females. The association of cancer with serum iron and transferrin tended to be stronger among women, whereas the association with serum copper tended to be stronger among men [165]. One study found higher serum iron concentrations in individuals with colorectal cancer than control subjects [9]. However, the evidence for a relationship between dietary iron intake and cancer, particularly colorectal cancer in the general population, is inconclusive, with reports linking high dietary Fe and Cu to colorectal cancer [166, 167] and a more recent study founding a non-significant inverse association for dietary iron and colorectal cancer risk, and a significant inverse association for serum ferritin and colorectal cancer risk. In this study, serum ferritin, serum iron and transferrin saturation were all inversely associated with colon cancer risk specifically, but not rectal cancer risk, whereas serum serum unsaturated iron binding capacity was associated with a greater risk for colon cancer [168].


There is a clear evidence linking over production of free radical species and the risk of cancer development. Oxidative damage to DNA can cause single point mutations which, when undetected and unrepaired by enzyme repair systems, can lead to transversion mutations, and errors in the DNA sequence. Indeed the chemical properties of some transition metals suggests a role for them in carcinogenesis. Fe or Cu can generate the reactive oxygen species including hydroxyl radicals via Fenton- and Haber-Weiss-reactions, ascorbate autoxidation, lipid peroxidation processes, and formation of DNA strand breaks [169, 170]. Several mechanisms have been proposed to explain the carcinogenic potential of iron. First, ferric ions are reduced by superoxide and the ferric product is reoxydized by peroxide to yield hydroxyl radicals which can attack DNA causing point mutations, DNA cross linking and DNA strand breaks. Second, iron can bolster the growth of cancer cells by suppressing host defenses. Finally, being an essential micronutrient, iron is important tumour cell multiplication [161].

It has been suggested that three predominant mechanisms generally account for carcinogenicity: (1) interference with cellular redox regulation and induction of oxidative stress, which may cause oxidative DNA damage or trigger signaling cascades leading to stimulation of cell growth; (2) inhibition of major DNA repair systems resulting in genomic instability and accumulation of critical mutations; (3) deregulation of cell proliferation by induction of signaling pathways or inactivation of growth controls such as tumor suppressor genes. In addition, specific metal compounds exhibit unique mechanisms such as interruption of cell-cell adhesion by cadmium, direct DNA binding of trivalent chromium, and interaction of vanadate with phosphate binding sites of protein phosphatase [171].

In our opinion it is thus possible to categorize transition metals that has been suspected in the process of carcinogenesis into two categories depending on their reactivity. The first of them are the oxidizing ones i.e., metals that have high oxidation number which can liberate free radicals via the Fenton reaction eg., [VO3]1-, [CrO4]2-,[FeO2]1-,[CuO2]2- or V5+, Cr6+, Fe3+ and Cu2+. The second group of them includes the soft and borderline (between soft and hard) metals that can react with the antioxidant compounds containing SH or OH reactive groups such as glutathione and picolines. These metals are namely Cu2+, Fe2+, Co2+, Ni2+ and Zn2+. Thus Fe3+complexes can react with H2O2 to produce free radicals while Fe2+an react with the antioxidant glutathione thus impairing antioxidant defense mechanisms increasing the vunerability of the cell to carcinogenic stimuli. It should also be noted that As5+ reacts with H2O2 leading to the formation of As3+ + H2O + O-2. (the latter species is a highly reactive one which can lead to DNA alterations).

Role of Transition Elements in Some Neurodegenerative Diseases The brain contains a relatively high concentration of a number of metals such as Fe, Zn,

and Cu (in the order of 0.10.5 M) [172]. Metal ions, particularly redox-active metal ions like copper and iron are the transition metals of marked significance in human disease and have been reported to accumulate in particular brain regions with aging [173]. An increase in their tissue concentration has been associated with the development of two important human diseases; haemochromatosis and Wilson's disease. The former is characterized by a genetic predisposition to an increased absorption of enteral iron with a consequent increased iron


level in the blood and tissues [174]. Wilson's disease, is a disorder of copper metabolism in which copper accumulation in tissues causes liver inflammation, fibrosis and neurologic complications including movement and psychiatric disorders [175]. Under these pathological conditions, transition metals and their transport proteins may accumulate in different target organs inducing cellular lipid peroxidation and DNA-attack. Redox active metals such as Cu, Fe and Mn can result in metal-catalyzed protein oxidation, while metal-protein associations can result in protein aggregation [176]. Recently, there has been much interest in the contribution to transition metals and in particular iron and copper to neurodegenerative diseases which will be highlighted in the following sections. We will focus on two well known and indeed the most common brain diseases namely Alzheimer's disease and Parkinson's disease.

Fe()+O2- Fe()+ O2 Fe()+ H2O2 Fe() +OH +OH- Cu()+O2- Cu()+ O2 Cu()+ H2O2 Cu() +OH+OH- 2O2-+2H+ H2O2 +O2 Cu2++ H2O2 OH + Cu1+

TRANSITION METALS AND ALZHEIMER'S DISEASE This progressive neurodegenerative disorder is characterized by a profound memory

impairment and cognitive decline [177, 178] which is associated with loss of central cholinergic neurons in the neocortex. The disease is estimated to affect 15 million people worldwide. The most common risk factor is age with an incidence of 0.5% per year at the age of 65 years to nearly 8% per year after the age of 85 years [179]. Most cases (95%) are sporadic, with only 5% of genetic origin. Neuropathologically, there is gliosis and tissue atrophy, most pronounced in the frontal and temporal cortices [180]. The disease is also characterized by the presence of amyloid beta (A) senile plaques and neurofibrillary tangles as well as dystrophic neuritis and degenerating neurons [181]. Senile or neuritic plaques consist principally of extracellular deposites of an ~ 4.3 kDa polypeptide, amyloid (A) peptide, derived from the proteolytic cleavage of the amyloid precursor protein (APP), a membrane bound normal protein molecule with 771 amino acids produced by neuronal and non-neuronal cells [182-184]. (forms when an alternative (beta-secretase and then gamma-secretase) enzymatic pathway is utilized for processing.). The A peptide can be between 39 and 43 residues in length. Neuritic plaques are composed of an extracellular core of filaments that measure 5-10 nm in diameter and are surrounded by dystrophic neurites and other debris, as well as microglial cytoplasmic processes and astrocytic processes containing glial filaments. Dense bodies, autophagic vacuoles and other membranous debris are common [185]. Neurofibrillary tangles are intracellular aggregates of a hyperphosphorylated form of the microtubule associated protein "tau", whose function is to regulate microtubule assembly and helps stabilize stabilize the neuronal microtubule skeleton [186].

Strong evidence implicates transition metals such copper, iron, and zinc in the pathophysiology of Alzheimers disease. In this respect, copper appears to have an important


role, though zinc as well as iron have also been implicated. Increased iron was found within the glial cells surrounding the neuritic plaques [187](Cu2+ is soft acid whereas Zn2+ and Fe2+ are borderline ones). High concentrations of copper (0.4 mM), zinc (1 mM) and iron (1mM) have been found within amyloid plaques [188]. In red blood cells patients affected by Alzheimer's disease, levels of Cu, Zn SOD activity increased early in the disease [189]. Studies suggested increased Zn in hippocampus, amygdala, and multiple neocortical areas of patients with Alzheimers disease [190-192]. More recent studies suggest a significant decrease of serum Zn in men with mild cognitive impairment (which accompany normal aging) (MCI

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