Molecular and ionic mimicry and the transport of toxic metals

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Abstract

Despite many scientific advances, human exposure to, and intoxication by, toxic metal species continues to occur. Surprisingly, little is understood about the mechanisms by which certain metals and metal-containing species gain entry into target cells. Since there do not appear to be transporters designed specifically for the entry of most toxic metal species into mammalian cells, it has been postulated that some of these metals gain entry into target cells, through the mechanisms of ionic and/or molecular mimicry, at the site of transporters of essential elements and/or molecules. The primary purpose of this review is to discuss the transport of selective toxic metals in target organs and provide evidence supporting a role of ionic and/or molecular mimicry. In the context of this review, molecular mimicry refers to the ability of a metal ion to bond to an endogenous organic molecule to form an organic metal species that acts as a functional or structural mimic of essential molecules at the sites of transporters of those molecules. Ionic mimicry refers to the ability of a cationic form of a toxic metal to mimic an essential element or cationic species of an element at the site of a transporter of that element. Molecular and ionic mimics can also be sub-classified as structural or functional mimics. This review will present the established and putative roles of molecular and ionic mimicry in the transport of mercury, cadmium, lead, arsenic, selenium, and selected oxyanions in target organs and tissues.

Introduction

Metals, including essential and nonessential species, make up a significant fraction of all elements. Nutritive (essential) metals, such as copper (Cu), zinc (Zn), and iron (Fe), are required for normal cellular processes in both prokaryotes and eukaryotes, and thus, there are mechanisms in place to regulate their cellular uptake and accumulation. In contrast, toxic (nonessential) metals, such as mercury (Hg), cadmium (Cd), and lead (Pb) have no known nutritive value. Accordingly, no specific, dedicated mechanisms have evolved for their uptake, at least in most animal species. Yet, many studies have proven that these toxic metals do indeed gain entry into various target cells (for reviews, see Clarkson, 1993, Ballatori, 2002, Zalups, 2000a, Zalups and Ahmad, 2003).

A number of different mechanisms for the transport of toxic metal species exist in the animal kingdom. In recent years, the concepts of molecular mimicry and ionic mimicry have been postulated as mechanisms by which certain toxic metal species can gain entry into target cells. The term, “mimic” is defined by Webster's 3rd New International Dictionary of the English Language (2002) as a verb meaning “to copy or imitate very closely.” Molecular mimicry refers to the phenomenon whereby the bonding of metal ions to nucleophilic groups on certain biomolecules results in the formation of organo-metal complexes that can behave or serve as a structural and/or functional homolog of other endogenous biomolecules or the molecule to which the metal ion has bonded (Fig. 1; Ballatori, 2002, Clarkson, 1993, Zalups, 2000a). Ionic mimicry, on the other hand, refers to the ability of an unbound, native, cationic species of a metal to mimic an essential element or cationic form of that element (Clarkson, 1993, Wetterhahn-Jennette, 1981, Zalups and Ahmad, 2003). Molecular and ionic mimics may be classified as structural and/or functional mimics. A structural mimic refers to an elemental or molecular species that is similar in size and shape to another element or molecule. A functional mimic is one that can elicit the same effect (i.e., physiological response) as the native element or molecule. In the following sections, we discuss structural and functional mimicry in relation to molecular and/or ionic mimicry and the specific metal involved in these phenomena.

It is thought that when metals bind to nucleophilic sites on certain biological molecules, the complexes formed are able to “mimic” structurally and/or functionally endogenous substrates that normally bind to, or occupy, the active sites of carrier proteins, channels, structural proteins, enzymes, and/or transcription factors. In recent years, a number of carrier proteins have been implicated in the transport of some toxic metals. In particular, amino acid transporters (i.e., system b0,+, system L; Bridges and Zalups, 2004, Bridges et al., 2004, Simmons-Willis et al., 2002) and organic anion transporters (i.e., OAT1 and OAT3; Aslamkhan et al., 2003, Zalups and Ahmad, 2004, Zalups et al., 2004) have been implicated in the absorptive transport of inorganic and organic forms of Hg in renal epithelial cells, endothelial cells and glial cells. Molecular mimicry has been implicated as the primary means for the entry of certain metals via these transporters. Interestingly, cationic forms of some metals can apparently mimic certain anionic complexes (i.e., oxyanions), as a form of molecular mimicry.

In principle, ionic mimicry is similar to molecular mimicry. The term ionic mimicry has, for the most part, been used to describe the ability of an unbound, cationic species of a metal to behave or serve as a structural and/or functional homolog or mimic of another (usually an essential) element at the site of a carrier protein, ion channel, enzyme, structural protein, transcription factor and/or metal-binding protein. For example, a great deal of evidence has been accrued showing that the cationic species of certain toxic metals, such as Cd, can use ion channels (in particular calcium (Ca2+) channels) and certain membrane transporters, such as the divalent metal transporter 1 (DMT1/DCT1/Nramp1), to gain access into target cells of mammalian organisms.

A considerable amount of scientific data on molecular and ionic mimicry has been published in recent years. Notwithstanding, numerous questions remain unanswered. This review will focus on known and putative mechanisms by which several toxic metals gain access to the intracellular compartments of target cells affected adversely by these metals. Evidence supporting the phenomena of molecular and/or ionic mimicry for selected toxic metals will be outlined individually by species of metal and the organs, tissues, and cells involved in the process.

Section snippets

Mercury

Hg is a unique toxic metal-pollutant that is found in many environmental and occupational settings. It can exist in elemental (metallic), inorganic, and/or organic forms. Elemental Hg (Hg0) is unique among all metals in that it exists as a liquid at room temperature. Due to its high vapor pressure, Hg0 can be released readily into the atmosphere as Hg vapor. Inorganic forms of Hg, as mercurous (Hg1+) or mercuric (Hg2+) ions, commonly combine with anionic species of chlorine, sulfur, or oxygen

Cadmium

Cd is a naturally occurring group IIB element found in the earth's crust. The ionic form of Cd (Cd2+) is usually combined with ionic forms of oxygen (cadmium oxide, CdO), chlorine (cadmium chloride, CdCl2), or sulfur (cadmium sulfate, CdSO4). Approximately 30,000 tons of Cd are released into the atmosphere each year, with an estimated 4000 to 13,000 tons coming from human activities. Since Cd2+ does not break down in the environment, the risk of human exposure is increasing constantly (ATSDR,

Lead

Lead (Pb) is a bluish-gray metal that occurs naturally in the earth's crust. It can exist as a Pb salt or as metallic Pb. Humans continue to be exposed to Pb through many different means. During the years when leaded gasoline was the primary source of fuel for automobiles, large quantities of Pb were added to the environment, especially in proximity to the major highways and thoroughfares. Additionally, up until 1978, much of the paint used in homes contained as much as 40% Pb (ATSDR, 2003c).

Selenium

Selenium (Se) is an essential element that is commonly found in rock formations and soil. It is rarely found in its elemental form in the environment, but is usually present as sodium selenite and sodium selenate. Se is essential for the proper function of intracellular antioxidant enzymes and has a recommended daily allowance of 55 μg/day (ATSDR, 2003d). This metal is not classified as a toxic metal, but rather, is considered to be essential for human health. Yet, it is unique in that it has

Arsenic

Arsenic (As) is a highly toxic element found naturally in the earth's crust. When combined with anionic species of oxygen, chlorine, or sulfur, it is referred to as inorganic As (ATSDR, 2003e). Organic As is formed when As ions combine with carbon and hydrogen. Data from studies of animals have shown that organic forms of As are less toxic than the same dose of inorganic As (ATSDR, 2003e). Interestingly, high doses of organic As can produce the same toxicological effects as a lower dose of

Oxyanions of toxic metals

It has been noted that endogenous oxyanions, such as monovalent phosphate and sulfate, are similar structurally to oxyanions of several toxic metals (Clarkson, 1993, Wetterhahn-Jennette, 1981). The molecular structure of arsenate and vanadate are very similar to that of monovalent phosphate, while the molecules, chromate, molybdate and selenate are similar in shape and size to sulfate (Fig. 1). Therefore, it is not surprising that the oxyanionic forms of toxic metals have been found to mimic

Summary

As humans are exposed to toxic metals in the workplace and environment, it is imperative that we understand how these metals affect essential cellular processes, and ultimately, human health. Molecules containing toxic metals have found ways to mimic endogenous molecules in order to gain access to target cells via essential transporters. Furthermore, some metals have been shown to mimic endogenous intracellular molecules, thereby interfering with essential cellular processes. Understanding how

Acknowledgments

This work was supported, in part, by the National Institutes of Health (NIEHS) grants, ES05980, ES05157, and ES11288, awarded to Dr. Zalups. Dr. Bridges is supported by a Ruth L. Kirschstein National Research Service Award, ES012556, funded by the National Institutes of Health (NIEHS).

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