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Review
. 2005 May 1;204(3):274-308.
doi: 10.1016/j.taap.2004.09.007.

Molecular and ionic mimicry and the transport of toxic metals

Christy C Bridges  1 , Rudolfs K Zalups
Affiliations
Review

Molecular and ionic mimicry and the transport of toxic metals (V体育平台登录)

VSports注册入口 - Christy C Bridges et al. Toxicol Appl Pharmacol. .

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 VSports手机版. .

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Fig. 1
Fig. 1
Space-filled models of selected mercuric conjugates and oxyanions implicated in molecular mimicry. Note the similarities in chemical structure between the cysteine (Cys) S-conjugate of methylmercury (CH3Hg-S-Cys) and the amino acid methionine. Also, note the similarities between the Cys S-conjugate of inorganic mercury (Cys-S-Hg-S-Cys) and amino acid cystine, and the homocysteine (Hcy) S-conjugate of inorganic mercury (Hcy-S-Hg-S-Hcy) of homocystine. A significant body of current evidence supports the hypothesis that mercuric conjugates of certain amino acids (such as Cys and Hcy) may act as molecular mimics of naturally occurring amino acids that are similar structurally to the mercuric complexes. Recent experimental findings from renal proximal tubular cells, transfected Madin-Darby canine kidney (MDCK) cells and oocytes from Xenopus laevis have demonstrated that Cys-S-Hg-S-Cys and Hcy-S-Hg-S-Hcy can act as molecular mimics of cystine and homocystine, respectively, at the sites of the luminal amino acid transporter, system b0,+ and the basolateral organic anion transporter, OAT1. There is also evidence from cultured endothelial cells and Xenopus laevis indicating that CH3Hg-S-Cys can serve as a molecular mimic of the amino acid methionine at the site of system L, which can explain the movement of methylmercury across the endothelium of the blood–brain barrier. There are also similarities in structure between monovalent phosphate and the oxyanionic forms of the toxic metals, arsenic (arsenate) or vanadium (vanadate). Both arsenate and vanadate have been shown to mimic phosphate at the site of phosphate transporters. In addition, the structure of sulfate is shown in comparison with the structures of selenate, molybdate, and chromate, which are homologous to sulfate. There is evidence indicating that these oxyanions can mimic sulfate at the site of transporters responsible for its uptake.
Fig. 2
Fig. 2
Diagrammatic representation of the transport of amino acids and mercuric conjugates of amino acids by the amino acid transporter, system b0,+ (A) and the organic anion transporter 1 (OAT1; B). (A) System b0,+ is a Na+-independent transporter comprised of a heavy chain and a light chain, which are linked together by a disulfide bond (S–S). The light chain, b0,+ AT (blue cylinders), possesses 12 transmembrane domains, while the heavy chain, rBAT (red cylinder), traverses the plasma membrane only once. This carrier is localized in the luminal plasma membrane of transporting epithelia (such as renal proximal tubular epithelial cells) and functions as an amino acid exchanger that mediates the transport of cystine as well as a variety of neutral and cationic amino acids. Recent studies have identified additional substrates for this carrier, including mercuric conjugates of cysteine (Cys; Cys-S-Hg-S-Cys) and homocysteine (Hcy; Hcy-S-Hg-S-Hcy), which are similar structurally to the amino acids cystine and homocystine, respectively. Experiments carried out in Madin-Darby canine kidney (MDCK) cells transfected stably with both subunits of system b0,+ showed that Cys-S-Hg-S-Cys and Hcy-S-Hg-S-Hcy mimic cystine and homocystine, respectively, at the site of this transporter. (B) The organic anion transporter 1 is a multi-specific carrier that is localized in the basolateral plasma membrane of many types of epithelial cells. Its expression is especially pronounced in renal proximal tubular epithelial cells. This transporter spans the plasma membrane 12 times and has two large intracellular loops, with the first between the first and second transmembrane domains and the second joining the sixth and seventh domains. The inward transport of organic anions is driven by the outward flux of α-ketoglutarate (α-KG). Data from recent studies in which MDCK cells were transfected stably with OAT1 demonstrate that mercuric conjugates of N-acetylcysteine (NAC-S-Hg-S-NAC), Cys-S-Hg-S-Cys, and Hcy-S-Hg-S-Hcy are transportable substrates of this carrier. As hypothesized for system b0,+, these mercuric species likely act as molecular mimics of endogenous substrates of OAT1.
Fig. 3
Fig. 3
Schematic representation of the transport of methylmercuric conjugates of cysteine (Cys; CH3Hg-S-Cys) by the amino acid transporter system L in the capillary endothelium of the blood–brain barrier. System L is a heterodimeric transporter that has been shown to mediate the Na+-dependent transport of a variety of large, neutral amino acids, including methionine, phenylalanine, leucine, and isoleucine. This transporter is an amino acid exchanger whose activity is dependent on the disulfide linkage (S–S) between the heavy chain 4F2hc and a light chain LAT1 or LAT2. System L has been identified in the basolateral plasma membranes of numerous types of transporting epithelia. Interestingly, it has been localized in the apical and basolateral plasma membranes of the endothelial cells lining the blood–brain barrier. Moreover, system L has been shown recently to take up and transport CH3Hg-S-Cys across this endothelial lining. Inasmuch as CH3Hg-S-Cys is similar structurally to the amino acid methionine, it has been suggested that this conjugate acts as a molecular mimic of methionine at the site of system L.
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