ABSTRACT
Every environmental and biological niche on earth is accessible to heavy metals. They enter into, and accumulate in, many of those compartments as the most long-lived product of both natural and man-made sources [1]. Metal ions are undoubtedly toxic to cells and organs in varying degree, but they are also required for viability by all living systems. For example, copper is essential for the function of oxidative enzymes (including catalase, peroxidase, cytochrome oxides, and others) but is also a cellular toxicant through its capacity to generate oxygen and other radicals that react with and diminish or destroy the function of essential cellular macromolecules [2]. The dual capacity to both induce damage and mediate essential physiological events is re ected in the development of cellular mechanisms to (a) transport metals into cells and subcellular compartments, (b) secrete
6.1 Introduction .......................................................................................................................... 143 6.2 MT Proteins .......................................................................................................................... 144 6.3 MT Gene Structure and Function ......................................................................................... 145
6.3.1 MT Gene Promoter Elements ................................................................................... 146 6.3.1.1 Basal MT Gene Transcription ................................................................... 146 6.3.1.2 Induced MT Gene Transcription ............................................................... 146 6.3.1.3 Metal Response Element-Binding Transcription Factor-1 (MTF-1) .......... 147 6.3.1.4 Oxidative Stress Induction ......................................................................... 149 6.3.1.5 Glucocorticoid Induction ........................................................................... 149 6.3.1.6 Cytokine and Stress-Mediated Induction .................................................. 149 6.3.1.7 Epigenetic Events: Chromatin Structure and DNA Methylation ............... 150 6.3.1.8 Post-Transcriptional Regulation ................................................................. 150 6.3.1.9 Developmental and Tissue-Speci c MT Expression ................................. 151
6.4 MT Function ......................................................................................................................... 151 6.4.1 MTs as Zinc Buffers ................................................................................................. 151
6.5 MT in Health and Disease .................................................................................................... 153 6.5.1 MT in Immune Function .......................................................................................... 153 6.5.2 MT and Cancer ......................................................................................................... 153 6.5.3 MT and Cardiac Toxicity .......................................................................................... 155
6.5.3.1 MT, Diabetes, and Cardiac Toxicity .......................................................... 155 6.5.4 MT and Neurological Function ................................................................................ 156
6.6 Summary and Perspective .................................................................................................... 157 Acknowledgment ........................................................................................................................... 157 References ...................................................................................................................................... 158
metals into the extracellular environment, and (c) associate metal ions with chaperone macromolecules that aid in those transport processes, control or abrogate their toxicity, and regulate metal ion availability for physiological processes. These events have been assumed to function to control metal toxicity, but recent evidence indicates that they also regulate the function of proteins that associate with metals (because those proteins depend on metal ions for function and/or they act as metal ion sensors important in regulating cellular events triggered by high or low metal ion levels in cells and cellular compartments). For metal ions that are essential and with low capacity to induce damage under normal circumstances (e.g., zinc) this may be especially true. More than 3% of the human genome encodes proteins with zinc-binding domains important for function and the fraction may be as high as 10% [3,4]. The large fraction of the human genome devoted to proteins encoding zincbinding proteins is re ected in the absolute requirement of zinc for life in a broad range of organisms. Like other Group IIB metal ions, zinc is capable of mediating redox reactions for biological purposes. It has the advantage of being relatively (but not completely) nontoxic compared to other metal ions, and that advantage is re ected in the many proteins that utilize zinc to coordinate protein-protein and protein-nucleic acid interactions (zinc ngers and zinc clusters, and nuclear hormone receptors) [5,6]. Severe zinc de ciency, although rare in humans, contributes to growth retardation, hypogonadism, dermatitis, and immune dysfunction [7]. Mild zinc de ciency, which has been suggested to be a health crisis of global proportions [8], has been linked to poor neuropsychological performance, abnormal fetal development (low birth weight and increased incidence of childhood disease in developing countries [9]), increased cancer risk [10-12], and overall increases in disease and resulting mortality [13,14]. Zinc availability, and zinc participation in physiological events mediated by zinc-binding proteins, is homeostatically regulated in organisms by controlled and mutually responsive interactions among an array of transporters that ef ux and import zinc (reviewed by Haase and Maret, this volume), transcription factors (including metal-responsive transcription factor-1 [MTF-1]) that both require zinc for activity and mediate cellular response to alterations in levels of biologically available zinc, and zinc storage vesicles (zincosomes) [15]. Mutations in zinc transporter genes aggravate the consequences of dietary zinc de ciency, or lead to pathological conditions arising from inadequate zinc regulation, independent of the amount of zinc in diet. For example, Acrodermatitis enteropathica is a rare condition involving zinc de ciency and is due to the presence of a mutated human Zip4 (SLC39A4) zinc importer [16,17]. Transient neonatal zinc de ciency (caused by low zinc levels in maternal milk) is caused by a mutation in the human ZnT2 zinc exporter [18]. Transport systems shuttle zinc into and out of cells and organs at a relatively high rate: in humans, approximately 1% of zinc in the body is replaced daily by the zinc obtained from dietary sources [19]. The primary site of zinc uptake is through intestinal enterocytes, while zinc excretion is by pancreatic acinar cells and other intestinal secretions. The expression of speci c zinc transporters (and the rate of zinc uptake and excretion) is responsive to dietary zinc levels and is coupled to regulated expression and action of intracellular proteins that associate with zinc, particularly metallothioneins (MTs). MTs have been implicated in a variety of functions, foremost of which is homeostatic regulation of zinc. In this chapter, we review the function and regulation of expression of MTs in the context of other proteins important in zinc regulation and the evidence for a homeostatic role for MTs in zinc metabolism.
