Transport of toxic metals by molecular mimicry.

Abstract

Intracellular concentrations of essential metals are normally maintained within a narrow range, whereas the nonessential metals generally lack homeostatic controls. Some of the factors that contribute to metal homeostasis have recently been identified at the molecular level and include proteins that mediate import of essential metals from the extracellular environment, those that regulate delivery to specific intracellular proteins or compartments, and those that mediate metal export from the cell. Some of these proteins appear highly selective for a given essential metal; however, others are less specific and interact with multiple metals, including toxic metals. For example, DCT1 (divalent cation transporter-1; also known as NRAMP2 or DMT1) is considered to be a major cellular uptake mechanism for Fe(2+) and other essential divalent metals, but this protein also mediates uptake of Cd(2+), Pb(2+), and possibly of other toxic divalent metals. The ability of nonessential metals to interact with binding sites for essential metals is critical for their ability to gain access to specific cellular compartments and for their ability to disrupt normal biochemical or physiological functions. Another major mechanism by which metals traverse cell membranes and produce cell injury is by forming complexes whose overall structures mimic those of endogenous molecules. For example, it has long been known that arsenate and vanadate can compete with phosphate for transport and metabolism, thereby disrupting normal cellular functions. Similarly, cromate and molybdate can mimic sulfate in biological systems. Studies in our laboratory have focused on the transport and toxicity of methylmercury (MeHg) and inorganic mercury. Mercury has a high affinity for reduced sulfhydryl groups, including those of cysteine and glutathione (GSH). MeHg-l-cysteine is structurally similar to the amino acid methionine, and this complex is a substrate for transport systems that carry methionine across cell membranes. Once MeHg has entered the cell, some of it binds to GSH, and the resulting MeHg-glutathione complex appears to be a substrate for proteins that mediate cellular export of glutathione S-conjugates, including the apically located MRP2 (multidrug resistance-associated protein 2) transporter, a member of the adenosine triphosphate-binding cassette protein superfamily. Because other toxic metals also form complexes with endogenous molecules, comparable mechanisms may be involved in their membrane transport and disposition.

Validity of methyl mercury hair analysis: mercury monitoring in human scalp/nude mouse model

“…Studies of MeHg transport and accumulation in endothelial cells of the blood-brain barrier and secretion from liver cells (Kerper et al, 1992;Ballatori, 2002) demonstrated that mercury is carried across cell membranes as a complex with small molecular weight endogenous thiol containing molecules. Specifically methyl mercury enters the cells as a complex with the amino acid L-cysteine and exits the cells as a complex with reduced glutathione.…”

Molecular and ionic mimicry and the transport of toxic metals

“…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).…”

“…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).…”

Manila clam Venerupis philippinarum as a biomonitor to metal pollution

“…Furthermore, Cd induces oxidative stresses by producing reactive oxygen species (ROS), which cause damage to biological molecules such as lipids, proteins and DNA (Chappie et al, 1997;Dovzhenko et al, 2005). Although zinc (Zn) is an essential element for organisms, excessive Zn can induce potential toxicities such as genotoxicity and immunotoxicity resulting in deleterious effects on fertilization, sexual maturity, and growth of the organisms (Münzinger et al, 1988;Ballatori et al, 2002;Murphy et al, 2011). In fact, improperly treated wastewater has led to severe contamination of Cd and Zn in the Bohai Sea (Zhang, 2001;Mao et al, 2009), which demonstrates the importance of monitoring these metal elements in this habitat.…”