“”This is a useful book which addresses many important issues that may not be addressed in more general textbooks. It is written in clear and simple language, which makes it highly readable and accessible to students and interested lay people…””

“This is a useful book which addresses many important issues that may not be addressed in more general textbooks. It is written in clear and simple language, which makes it highly readable and accessible to students and interested lay people…”

Trace Element Medicine and Chelation Therapy

By David M. Taylor, David R. Williams

The Royal Society of Chemistry

Copyright © 1995 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-0-85404-503-7

Contents

Chapter 1 Introduction, 1,
Chapter 2 The Elemental Composition of the Human Body, 16,
Chapter 3 Metal Ions, Complexes, and Chemical Speciation, 26,
Chapter 4 Chelation, Ligands, and Drugs, 42,
Chapter 5 Delivery of Trace Elements to Humans, 50,
Chapter 6 Agents Containing Metals, 57,
Chapter 7 Chelating Agents and Therapy, 77,
Chapter 8 Dietary and Environmental Aspects, 98,
Chapter 9 The Future, 117,
Subject Index, 119,

CHAPTER 1

Introduction

WHAT IS LIFE?

Life is a complex process that as yet defies accurate scientific definition. The eminent biochemist, and Nobel Laureate, Christian de Duve has described life as a system which is able ‘to maintain itself in a state far from equilibrium, grow, and multiply, with the help of a continual flux of energy and matter supplied by the environment’. In amplification of this description de Duve defines ‘seven pillars of life’ which are necessary and sufficient for all forms of life. Thus any living system must have the ability to:

1. Manufacture its own constituents from materials available from its surroundings;

2. Extract energy from its environment and convert it into the different forms of work that need to be performed to stay alive;

3. Catalyse the numerous chemical reactions required to support its activities;

4. Inform its biosynthetic and other processes about how to guarantee accurate reproduction;

5. Insulate itself in such a way that it keeps strict control over its exchanges with its external environment;

6. Regulate its activities in order to preserve its dynamic organization in the light of environmental changes;

7. Multiply itself.

Implicit within this statement is the fact that life is dependent on the laws of nature, which are both imperative and inescapable: these laws mean that the development of any living system, or part of any such system, is entirely dependent on the biochemical milieu in which it develops. The statement also contains a paradox in that the definition states that the living system is in a state far from equilibrium, yet ‘pillars five and six’ demand that the reactions and processes essential for life strive to maintain themselves in a quasi-steady state. The essential components of the biochemical milieu must be supplied from the environment in the form of foodstuffs, gases, and water.

The basic unit of life is the cell and the simplest living sytems are single cells that possess all the above capabilities, drawing their building materials from simple chemical substances in their, generally aqueous, environment. More complex life forms, for example, Homo sapiens, are multicellular organisms in which every cell does not possess all of the ‘seven pillars of life’ and life is possible only because the cells form a society whose health is dependent on the integrated activities of the different cell types within the system. In the human body there are some 1015 such cells.

It has been known for many years that healthy human, or animal life, requires the provision of adequate quantities of numerous organic substances (for example, proteins, sugars, fatty acids, and vitamins) and of such inorganic ingredients as calcium and iron. However, the requirement for many other inorganic elements went unrecognized for a long time because they are present in human tissues and in foodstuffs in very low concentrations. Fortunately, the natural content of these trace elements in food, or in soil impurities clinging to some foodstuffs, were generally sufficient to meet human needs so that health-impairing deficiencies occurred only relatively rarely. However, with people living much longer and with the often highly refined foods in our diet, long-continued, marginally sub-optimal intakes of essential or beneficial metals may over long periods lead to serious deficiency symptoms. This is not to be interpreted as a recommendation for us to become health food fanatics.

More recently, due in no small part to improvements in chemical analysis, metal deficiency diseases have become more widely recognized and this has focused the attention of laboratory researchers in biochemistry, inorganic chemistry, clinical medicine, and pharmacology upon the exact determination of elemental concentration (in order to establish the elemental status of the patient) and on the mechanisms involved in the bio-availability, assimilation, and excretion of trace elements, some of these conditions are illustrated in the colour plates (Plates 1–8, pages 2–5). Even more recently pathological conditions arising from trace element excess have come to light, perhaps because environmental pollutants have been suspected of causing symptoms in people living or working in a specific area. Trace element deficiency syndromes are not always mirrored in wild animals because, living in a natural habitat, they tend to acquire their trace elements from both their diet and from soil particles eaten with their food, thus they may avoid the deficiencies or excesses which can arise from our consumption of standardized, purified, and processed foods and can lead to the so-called ‘diseases of civilization’.

The aim of this book is to consider the importance of trace elements for the maintenance of human health and to illustrate the relationships between inorganic chemistry, biochemistry, and medicine (Figure 1.1). This is achieved through discussions of how a deficiency, or an excess of metals, may cause disease; how drug-induced interference with the natural metal binding mechanisms in tissues may be used to treat illnesses; and how, in cases of metal overload, chelation therapy with powerful ligands may be used to reduce the risks of serious health effects by accelerating the natural rate of excretion of the offending metal.

EVOLUTION

The origin of life and its evolution into the life-forms we know today remains a contentious issue. This controversy arises mainly because there is a lack of hard scientific data, from fossils or other sources, on how primitive cells develop ( microbial evolution being about as far back as we can go). Cosmology and geochemical data suggest that the Earth was formed as a condensation product from gas and dust particles from an immense supernova in outer space some (4.5–4.7) x 109 years ago.

The geochemical theory of evolution suggests that the newly formed planet had a hard core and a reducing atmosphere containing H2O, H2 S, NH3, CH4, and perhaps some CO2 : over the next 109 years these substances were bombarded with energy, for example from the sun or from nuclear changes within the Earth’s crust or atmosphere, resulting in the formation of simple organic species. These then reacted with inorganic constituents to yield simple monomeric biochemicals (amino acids, sugars, nucleotides, etc.) and then biopolymers (proteins, starches, glycogen, and nucleic acids) and eventually to the first primitive cell which then required a further 3.5 x 109 years to evolve into life as we know it today; this evolution is illustrated diagrammatically in Figure 1.2.

Biochemical theory based on our knowledge of the rates of reaction of biological catalysts (enzymes) suggests, however, that the time from the development of protometabolism to the formation of the first oligonucleotides (nucleic acids) may in fact have required only a few thousands of years, at most a few tens of thousands of years, rather than the hundreds of millions of years implied from the geochemical data. A shorter period for the evolution of life means that there would not have been the same necessity for inordinately long periods of environmental stability and also that evolution could have been attempted in different places at different times.

Whatever the real time scale required for evolution, the process was a protracted and continuous progression from primitive, inefficient mechanisms to more complex, efficient ones. The reactions all occurred in the oceans, or along the shorelines, and metal ions must have played a critical role both in determining the compositions of the biopolymers we know today and in dictating whether the L- or D-configurations of sugars and amino acids would be preferred. The concept that tides produced anhydrous conditions on beaches dried by the Sun and wind and that reactions occurred in the structural grooves of ‘beach’ crystals, such as silicates or apatites (calcium phosphates) appears logical. The condensation of monomers into polymers requires the withdrawal of water molecules and such dehydration is extremely unlikely in the ocean unless a heterogeneous catalyst is present.

The primeval cell probably contained about 100 protein molecules, in contrast to the many millions of protein molecules in modern cells, and it certainly contained a variety of metal ions some of which fulfilled structural osmotic or catalytic roles. Magnesium would have been particularly good in this latter role since it is known to catalyse condensation reactions and to have been present in high concentration in primeval oceans (it is currently present in a concentration of 50 mmol dm-3 in modern sea water). The close similarity of the ionic composition of many of our body fluids and those found in sea water strongly supports the view that life evolved in, or from, the oceans.

Elemental analyses of several hundred plant and some two hundred, animal species have identified the elements present in biological systems and, in Periodic Table terms, these are generally relatively light, and are those elements which are found nearest the surface of the Earth’s crust (see Figure 1.3). The biologically essential metals are Na, K, Li, Mg, Ca, Mo, Mn, Fe, Co, Cu, and Zn and their ions all have potentially powerful complexing capabilities; some also possess important redox properties. Since the early atmosphere of the Earth was a reducing one, Mn(n) and Fe(n) would have been important in the primeval cell systems. In addition to the essential metals, some other elements are recognized as being beneficial to life, for example Si, V, Cr, Ni, Se, Sn, Br, and F (and possibly also As, B, Ba, Cd, and I) and these are believed to have become involved only in more recent, more highly organized life-forms.

It is signifcant that the human body has not yet evolved mechanisms to protect against overdoses of beneficial elements which are as effective as those which function to minimize or prevent the effects of overloading with many essential metals. For example, 0.1 p.p.m. of Se is beneficial while 10 p.p.m. may be carcinogenic (capable of causing cancer) . Recalling that the Periodic Table is founded upon the concept of relationships between elements, we may deduce that the strongest challenges to the normal cellular processes will come from elements having Periodic Table positions adjacent to essential and beneficial elements, for example the pollutants Cd and Hg with Zn, or Pb with Sn. It appears that these dangerous metal ions interact with the in vivo mechanisms through which essential trace elements operate and thus reduce or prevent the normal biochemical functions.

The metal ion composition of the human body has been dictated by several principles. The major role has been played by the abundance of metal ions in the hydrosphere, but, when metals possess redox properties, it is imperative to have an adequate supply of matched reducing and oxidizing ligands in order to maintain the oxidation state required for the particular biological mechanism (e.g. porphyrins to complex Fe(II) in the haem moiety) . When oxygen entered the atmosphere, mainly from the photosynthetic activity of blue-green algae, it was very toxic to most living systems because it tended to change the oxidation states of Mn (II), Fe(II) , Co(II) , and Cu (I) , etc. However, the cell soon adapted to protect itself against oxidation, principally through evolving peroxisomes which convert O2 to H2O2 and then to water. In the early days copper was trapped mainly as insoluble Cu (I) sulfides, but once an oxidizing atmosphere developed, Cu (II) could join Mg, Fe, and Mn as one of the primitive essential trace metals. At about the same time Fe and Mn became immobilized by the reactions:

Fe(II) [right arrow] Fe3O4(s) [right arrow] FeOOH(s)

and

Mn(II) [right arrow] Mn3O4(s) [right arrow] O2(s)

and the atmospheric ozone content crept up to about 1%, which is adequate to screen out the most harmful effects of the Sun’s ultraviolet radiation: the latter is apparently more destructive to aerobic than anaerobic metabolism. These changes allowed aerobic metabolism to replace anaerobic metabolism, some organisms using iron and others the newly released Cu (II) for oxygen assimilation.

Certain evolutionary constraints arose because of competition for metal complexing ligands in the primitive systems. Ca2+ and Cu2+ ions provide a good example of this phenomenon. When Ca2 + became available to the evolving system it was rapidly assimilated into the primitive biocatalysts, the protoenzymes, through binding to carboxylate groups. However Cu2+ complexed far more firmly to the abundance of amino acids inside the cells (Ca2+–amino acid interactions are weak) and it was only when the amino acids began to condense to form polypeptides that Cu2+ binding sites evolved which were powerful enough to overcome the fierce amino acid–Cu2+ complexing opposition that the Cu2+ proteins evolved. The evolution of the Cu (II)-specific binding sites was slow, requiring many generations of mutation. This principle of free amino acid ‘selectivity’ still operates today and forms part of the natural detoxication mechansims which complex polluting or contaminating metals thus rendering them less harmful to the organism than if they were bound to a biochemically critical site within an essential protein.

The main group metal ions Na+, K+, Ca2+, and Mg2+ possess closed-shell electronic structures and their roles in vivo have evolved to exploit their electrostatic bonding properties in preference to their covalent characteristics; therefore their charges and ionic radii have been important in bio- inorganic evolution. For example, their ions are strongly aquated with the following results: (a) when they form complexes many molecules of water are liberated and the bonds to the ligand are en tropy stabilized and (b) the highly ordered inner and outer solvation spheres of say Mg2+ and its high concentration within cells helps to produce the highly organized systems that modern cells exhibit.

It is interesting to note that Mg2+ ions have been present in cells from the very beginning whereas Ca2+ has only become essential in the later, more sophisticated species, for example those which require signal transmission along nerves and, perhaps, also a bony skeleton or a hard shell: Ca2+, therefore, like the beneficial elements mentioned earlier, is one of the ‘newer’ elements. Despite being essential for human life, Homo sapiens has not yet adapted or evolved to handle completely all the chemical problems raised by the presence of Ca2+ in the body, and its precipitates, as phosphates, oxalates, etc., all too commonly cause problems such as atherosclerosis, kidney or gall stones, and cataracts.

Some concluding comments to this brief survey of evolution are apposite:

1. The specificity of metals ions in the human body is extremely good. Why else will many of us function smoothly for 70 + years without need for ‘service, lubricant change, reprogramming or spare parts’?

2. Researchers into the origins of life and chemical evolution may perhaps have become over fascinated with the organic chemical aspects, tending to lose sight of the fact that from the time when simple molecules were washed onto ‘beach crystals’ and condensed into stereoisomers, the organic and the inorganic aspects of chemical evolution have progressed in hand.

3. Evolution took place under relatively constant environmental conditions, but more recently, within the last 3000 years, and especially the last 200 years, human activities such as mining, large-scale utilization of metals such as lead, mercury, and cadmium and the growth of the chemical, petrochemical, and other industries, have lead to quite serious local disturbances, and to much smaller global changes of the environment that have already been, or may yet be demonstrated to be seriously detrimental to many living systems. Some of the effects of metal pollution on human health will be discussed in the next chapter.

COMPOSITION AND STRUCTURE OF LIVING SYSTEMS

This book is concerned with bio-inorganic chemistry, i.e. the chemistry of reactions involving metals and other trace elements with the components of living cells and tissues. In order to consider the influence of metal ions, ligands, and metal complexes on human health we should first be able to envisage the basic composition and organization of living systems and the vast differences in scale in terms of the relative sizes and masses of the biological and chemical species we are discussing. Humans are dependent on species smaller than themselves and these, in turn, are dependent on even tinier species.

(Continues…)Excerpted from Trace Element Medicine and Chelation Therapy by David M. Taylor, David R. Williams. Copyright © 1995 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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