METAL IONS IN BIOLOGICAL SYSTEMS Edited by Astrid Sigel and Helmut Sigel Department of Chemistry Inorganic Chemistry University of Basel CH-4056 Basel, Switzerland VOLUME 41 Metal Ions and Their Complexes in Medication MARCEL DEKKER, INC., NEW YORK • BASEL FONT IS M E D IA DEKKER Copyright © 2004 by Marcel Dekker, Inc. All Rights Reserved. ISBN: 0-8247-5351-8 The figure on the dustcover is part of Figure 3B of Chapter 11 by H. Sun, L. Zhang, and K.-Y. Szeto. This book is printed on acid-free paper. This book is a joint publication of FontisMedia S.A. and Marcel Dekker, Inc. FontisMedia S.A. Avenue Vinet 19 CH-1004 Lausanne, Switzerland tel: 41-21-648-3971; fax: 41-21-648 39 75 WWW: http://www.fontismedia.com Headquarters Marcel Dekker, Inc. 270 Madison Avenue, New York, NY 10016 tel: 212-696-9000; fax: 212-685-4540 Eastern Hemisphere Distribution Marcel Dekker AG Hutgasse 4, Postfach 812, CH-4001 Basel, Switzerland tel: 41-61-261-8482; fax: 41-61-261-8896 World Wide Web http://www.dekker.com The publisher offers discounts on this book when ordered in bulk quantities. For more information, write to Special Sales/Professional Marketing at the headquarters address above. COPYRIGHT © 2004 BY MARCEL DEKKER, INC. ALL RIGHTS RESERVED. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher. Current printing (last digit): 10 9 8 7 6 5 4 3 21 PRINTED IN THE NETHERLANDS Copyright © 2004 by Marcel Dekker, Inc. All Rights Reserved. Preface to the Series Recently, the importance of metal ions to the vital functions of living organisms, hence their health and well-being, has become increasingly apparent. As a result, the long-neglected field of "bioinorganic chemistry" is now developing at a rapid pace. The research centers on the synthesis, stability, formation, structure, and reactivity of biological metal ion- containing compounds of low and high molecular weight. The metabolism and transport of metal ions and their complexes is being studied, and new models for complicated natural structures and processes are being devised and tested. The focal point of our attention is the connection between the chemistry of metal ions and their role for life. No doubt, we are only at the brink of this process. Thus, it is with the intention of linking coordination chemistry and biochemistry in their widest sense that the Metal Ions in Biological Systems series reflects the growing field of "bioinorganic chemistry". We hope, also, that this series will help to break down the barriers between the historically separate spheres of chemistry, biochemistry, biology, medicine, and physics, with the expectation that a good deal of future outstanding discoveries will be made in the interdisciplinary areas of science. Should this series prove a stimulus for new activities in this fascinating "field", it would serve its purpose and would be a satisfactory result for the efforts spent by the authors. Fall 1973 Helmut Sigel Department of Chemistry Inorganic Chemistry University of Basel CH-4056 Basel, Switzerland Copyright © 2004 by Marcel Dekker, Inc. All Rights Reserved. Preface to Volume 41 This volume on Metal Ions and Their Complexes in Medication opens with a general chapter on the Speciation Dependent Intake and Uptake of Essential Elements. When 'life' on this planet began about 3.5 billion years ago, the primitive cells evolving in oceans used the elements readily available in the ancient seas and sea-beds. This is still reflected in the composition of the modern human body, which resembles the composition of these primitive synthetic arenas, with the lighter elements of the periodic table (atomic no < 35) being dominant. These elements and their properties are shortly summarized in this introductory chapter and the importance of speciation, i.e., the occurrence of an element in separate, identifiable forms defining the oxidation state, concentration, and composition of each of the species present, is emphasized. Thus, speciation provides the explanation why some compounds, e.g., are 'taken up' and easily traverse membranes which others, despite their 'intake', don't. Speciation is clearly an interdisciplinary topic and its pivotal role in a healthy life and diet reflects the fact that 'the greater the challenge, the greater the need for metal ions' since 'whenever nature has a difficult task to perform, a metal ion (or a cluster of such ions) is invariably employed'. In accord herewith, in the first part of the volume benign metal ions, which are hardly toxic but can be deficient, are dealt with; e.g., magnesium(II) is an essential nutrient with a variety of pharmacological effects; it is beneficial inter alia in cardiovascular disorders, allergic reactions, and acute asthma. Calcium(II) is another example: about 99% of it are localized in the skeleton as hydroxyapatite, yet the extracellular Copyright © 2004 by Marcel Dekker, Inc. All Rights Reserved. ionized fraction is involved in many physiological functions, such as muscle contraction, neuronal activity, cellular permeability, hormone secretion, and enzyme activity. Considering that the daily intake may vary dramatically, even in a given population, calcium status and supplementation deserve recognition, also in view of the potential prevention of osteoporosis. This also holds for zinc(II), which was shown by Raulin in 1869 to be essential for the growth of Aspergillus niger, but only about 100 years later it became apparent that zinc deficiency in humans is quite prevalent and that supplementation, not only due to its positive effects on wound healing, may be desirable in certain instances. With iron the situation is quite different: both, deficiency and overload cause serious problems and indeed, disorders of iron metabolism in man are relatively common. Iron uptake in the presence of dioxygen, due to the special chemical properties of this element, is not trivial, as is illustrated by the fact that already Escherichia coli devotes nearly 50 genes to proteins involved in iron uptake. Since iron excretion in man is almost non-existent, iron balance is determined primarily by iron absorption even though a delicate balance, referred to as iron homeostasis, needs to be achieved. These difficulties including the potential applications of chelation therapy for the removal of toxic iron are discussed in Chapter 6. In the second part of the volume metal-based medications are considered such as the (potential) use of vanadium compounds in the treatment of diabetes mellitus, of copper and zinc complexes as antiinflammatory drugs, of gold complexes in the treatment of rheumatoid arthritis, and the medical use of lithium salts in the treatment of manic- depressive patients and beyond, as well as the role of bismuth compounds in medicine, in particular in gastrointestinal disorders. In fact, the use of metal complexes as chemotherapeutic agents has gained momentum in the last decades, mainly as a result of the success of cisplatin as an antitumor agent; this and related compounds are considered in the following volume (No 42) entitled Metal Complexes in Tumor Diagnosis and as Anticancer Agents. Unfortunately the use of metal complexes in the treatment of tropical parasitic diseases has not advanced to the same degree, despite the fact that these diseases have been identified among the most important world health problems. The present knowledge on Copyright © 2004 by Marcel Dekker, Inc. All Rights Reserved. metal-based chemotherapeutic agents against malaria, trypanosomiasis, and leishmaniasis is covered in Chapter 12. The terminating chapter of Volume 41 is devoted to another most fascinating topic, namely the use of Metal Complexes as Therapeutic Agents in Nitrogen Monoxide Modulation. One of the recent most significant discoveries in biological inorganic chemistry is the role that the simple diatomic nitrogen monoxide molecule (NO) has as a cell signalling and regulatory species in the cardiovascular system, and peripheral and central nervous system, and also as a component of the immune system. Indeed, disruption of the NO signalling pathway has been implicated in the pathophysiology of many disease states and this has led to studies on the potential use of metal complexes as NO donors as well as NO scavengers; the corresponding state of the art is evaluated in this chapter. Astrid Sigel Helmut Sigel Copyright © 2004 by Marcel Dekker, Inc. All Rights Reserved. Contents PREFACE TO THE SERIES PREFACE TO VOLUME 41 CONTRIBUTORS CONTENTS OF PREVIOUS VOLUMES HANDBOOK NO TOXICITY OF INORGANIC COMPOUNDS HANDBOOK ON METALS IN CLINICAL AND ANALYTICAL CHEMISTRY HANDBOOK ON METALLOPROTEINS Chapter 1 SPECIATION DEPENDENT INTAKE AND UPTAKE OF ESSENTIAL ELEMENTS Janette Davidge and David R. Williams 1. Introduction 2. Elements in Humans 3. Speciation 4. Optimizing Intakes and Uptakes 5. Commercial Element Supplementation 6. Conclusions Acknowledgments Abbreviations and Definitions References Chapter 2 MAGNESIUM IN HUMAN THERAPY Hans-Georg Classen, Heimo Franz Schimatschek, andKonrad Wink 1. Early Roots Copyright © 2004 by Marcel Dekker, Inc. All Rights Reserved. 2. Magnesium Therapy 3. Magnesium in Obstetrics and Gynecology 4. Magnesium in Pediatrics 5. Magnesium in Neurology and Psychiatry 6. Magnesium in Cardiovascular Disorders and Hypertension 7. Renal Magnesium Wasting 8. Magnesium and Allergic Reactions, Acute Asthma 9. Safety Aspects Abbreviations References Chapter 3 CALCIUM STATUS AND SUPPLEMENTATION Lasse Larsson and Per Magnusson 1. Introduction: General Importance of Calcium 2. Calcium Homeostasis 3. Disturbances in Calcium Absorption 4. Renal Regulation of Calcium 5. Bone and Mineral Metabolism 6. Genetics in Calcium Homeostasis 7. Calcium Intake and Supplementation 3. General Conclusions Abbreviations References Chapter 4 ZINC DEFICIENCY: ITS CHARACTERIZATION AND TREATMENT Ananda S. Prasad 1. Brief History of the Discovery of Zinc as an Essential Element for Human Health 2. Clinical Effects of Zinc Deficiency 3. Major Effects of Zinc Deficiency in Humans 4. Diagnostic Criteria for Zinc Deficiency 5. Therapeutic Uses of Zinc 6. Toxicity of Zinc Copyright © 2004 by Marcel Dekker, Inc. All Rights Reserved. 7. Conclusion Abbreviations References Chapter 5 THE USE AND ROLE OF ZINC AND ITS COMPOUNDS IN WOUND HEALING Paul W. Jones and David R. Williams 1. Introduction 2. The Anatomy and Functions of the Skin 3. The Physiology of Wound Healing 4. Zinc and Wound Healing 5. Wound Management Products and Treatments Containing Zinc 6. Innovations in Trace Element Based Wound Management 7. Conclusions Abbreviations References Chapter 6 IRON CHELATORS AND THEIR THERAPEUTIC POTENTIAL Robert R. Crichton and Roberta J. Ward 1. Introduction: The Importance of Iron in Biology and Medicine 2. Iron Metabolism and Its Disorders 3. Classes of Molecules with Potential for Iron Chelation Therapy 4. Potential Chelation Sites 5. Potential Applications of Chelation Therapy Acknowledgment Abbreviations References Chapter 7 VANADIUM COMPOUNDS IN THE TREATMENT OF DIABETES Katherine H. Thompson and Chris Orvig 1. Introduction 2. Insulin Resistance Copyright © 2004 by Marcel Dekker, Inc. All Rights Reserved.