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Book Review |
Dean, College of Agriculture, California State Polytechnic University, Pomona
Metal Ions in Biological System, Volume 36: Interrelations Between Free Radicals and Metal Ions in Life Processes. Astrid Sigel and Helmut Sigel, eds. New York: Marcel Dekker, Inc., 797 pp, 1999.
Numerous books have been published on free radical reactions, usually describing harmful cellular or membrane reactions, atherosclerosis, cancer initiation or aging processes. The present volume contains 21 chapters written by an international group of researchers, each well published in areas concerned with free radical reactions. The book is unique in both reviewing the basic chemistry of free radical reactions and integrating that knowledge into biological areas that remain poorly understood, among them, the sure prediction of those active-oxygen species which will exist under the conditions of a specific physiologic reaction. The book presents a range of opinions and interpretations of data. Thus, while laying out solid information, it enables the reader to develop his or her own perspective, thereby stimulating future research.
Early chapters review the basis of free radical reactions clearly, describing the processes leading to hydroxyl and superoxide radicals. Hydroxyl reactions (HO•) may be formed by Fenton-like reactions involving ferrous iron or other transition metals and hydrogen peroxide (H2O2), by absorption of ionizing radiation or UV light, or when ozone (O3) is introduced into a biological system. Superoxide (O2-) may form as a side product of the electron transport chains in mitochondria and the endoplasmic reticulum and by heme oxidation during oxygen transport. A greater understanding of free radical processes in vivo would enhance our ability to explain newly observed phenomena. Superoxide dismutase (SOD) dismutes O2- rapidly to O2 and H2O2, providing cellular protection from free radicals.
The role of transition metal complexes in the induction of biologically deleterious processes is proficiently discussed. These play a major role in the production of HO• radicals or endogenous oxidizing agents, via Fenton-like reactions, and probably in the catalysis of the Haber Weiss reaction of O2- with H2O2. Transition metal complexes react preferentially with secondary, aliphatic C-centered, and tertiary, alkyl-peroxyl, radicals formed in biological systems. These reactions direct the radical-initiated processes to biological sites where the transition metal complexes are located. They provide an alternative to the explanation offered by the site-specific effect. The products of radical reactions with transition metal complexes, especially those resulting from the decomposition of the transient complexes (LmMn+1-R and LmMn+1-OOR), are probably the cause of many biologically deleterious effects initiated by radicals. This area needs extensive additional experimental evaluation.
Dioxygen metabolism and free radicals are discussed in the third chapter, which reviews the basic redox chemistry of dioxygen, bond energies and acid base chemistry. The major radical species include hydrogen abstraction, chain autoxidation and Fenton-like reactions. Descriptions of lipid peroxidation through thermochemistry in this chapter provide increased insight into some of the reaction choices made in biological systems. The primary products, of course, are the lipid hydroperoxides. The chapter, however, indicates no direct link between the rate of reaction and its thermodynamic feasibility, a gap which makes prediction of reactions difficult.
Chapters stimulating further thought and research include those dealing with the link between CuZn-SOD and amyotrophic lateral sclerosis, which has been related to mutant and wild-type CuZn-SOD mouse models. Four separate mutations, resulting in dissimilar pathological expressions, yield the same result—death by motor neuron disease. Multiple properties of the mutant enzymes affect toxicity, including SOD peroxidation and nitration activities. Importantly, the authors note other factors that contribute to the disease in question.
Participation of metal ions in DNA damage has been associated with carcinogenesis, metabolic imbalance and several other pathologies. The conditions needed to cause single strand breaks by FeNTA in vitro are identical to conditions in the anatomic location where tumors appear after FeNTA treatment in vivo. Evidence is presented to determine the SSBs and DSBs mediated by metal ions and the protection offered by chelators, free radical scavengers and other substances at the onset of DNA damage. The reaction of DNA strand breakage and formation of 8-OHdG are identified and noted to be useful as markers for in vivo DNA breakage in disease. Each metal discussed appears to have its own specific target within the DNA sequence.
A series of intercalated reactants with different structural properties can undergo efficient electron transfer over long molecular distances through the DNA. The base stack (a molecular 
stack) can serve as a bridge medium that allows facilitation of long-range electronic coupling. This stack of aromatic heterocycles participates in chemical reactions triggered from remote locations along the DNA helix and is pertinent to biological base-damage mechanisms. Poorer electron transfer efficiency occurs through DNA in systems employing nonintercalating reactants. Thus, it may be imagined that the transmission of information by DNA, which is based on the structural characteristics of the DNA bases within the double helix, may be influenced by the electronic properties of these stacks and the transport of electrons through their interiors.
Lipid peroxidation is well recognized to be a critical stage in toxicological processes. Peroxidation of polyunsaturated fatty acids in lipid bilayer membranes causes loss of fluidity, a fall in membrane potential, increased permeability for protons and calcium ions and eventually loss of cell membranes. The structural and functional integrity of the cell membranes is necessary for cell survival and therefore must be preserved. During the course of these damaging processes, metal ions are involved in depletion of cellular antioxidants, activation of phagocytes, mitochondrial dysfunction, activation of microsomal enzymes and tissue damage related to fibrogenesis and atherogenesis.
Progress in understanding molecular pathogenesis of neurodegenerative diseases has shown metal binding and radical generation of proteins related to neurologic disease and aging in humans. Free radicals and metal ions, such as Zn(II), Fe(II), Cu(II) and A1(III), participate in the pathogenesis of Alzheimer’s disease. These metals accumulate in the neuropil of the AD brain and are enriched (at mM levels) in the amyloid deposits. Aß, the major component, avidly binds these metals. The global oxidative stress observed in AD may well be focused at the amyloid deposits due to accumulation of Aß and the presence of redox-active metal ions. Oxidative events convert Aß deposits to amyloid plaques. If so, then antioxidants and metal chelators may be of therapeutic value. 
-Tocopherol may slow early progression of AD. Other examples are provided, but many questions remain.
The role of free radicals in metal-induced carcinogenesis is discussed for Cr (V or VI), Ni, As, Be, Fe and Cu. As storage of these metals increases, so does the potential for carcinogenesis. Local variations of HO• in chromatin correlate to the carcinogenic potential of metal compounds. An approach using SECCA-binding to chromatin has been developed for detection and study of chromatin-associated, metal-catalyzed HO•, a subpopulation of HO•, that may be particularly important for chromatin damage, mutagenesis and carcinogenesis. This technology allows the analytical investigation of chromatin-associated HO• on chromosomal proteins and DNA and may provide a methodology for the estimation of the susceptibility of specific DNA sequences to metal-catalyzed HO• attack.
Other topic areas included in the book are biological roles for nitric oxide and nitrogen monoxide, the chemistry of peroxynitrate, nitrogen-monoxide-related diseases and the therapeutic modulation of nitric oxide.
Entries in the "Metals in Biological Systems" series have all been well-written, timely, thought-provoking and useful. This volume is just as creative and challenging as its predecessors. It will stimulate the interest of faculty and students alike in new areas of research related to biological systems.
Received May 1, 1999.
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