Transport of Organic Complexes

Recent studies demonstrate that toxic metals can enter cells complexed with endogenous organic ligands whose overall structures mimic those of native substrates for membrane transporters. In particular, membrane carriers for amino acids and glutathione may be responsible for the transport of some metals as mercaptides (Kerper et al. 1992 Dutczak and Ballatori 1994 Ballatori 1994). Although this mechanism had long been considered a theoretical possibility, direct experimental support at the cellular and sub-cellular level was lacking. 

Methylmercury transport across the blood-brain barrier appears to be mediated by the large neutral amino acid transport system (system L) on the luminal surface of brain capillary endothelial cells (Kerper et al. 1992). Previous in vivo studies had shown that the amino acid, L-cysteine, accelerates methylmercury uptake into brain in vivo, but the mechanism was not identified. Because the methylmercury-L-cysteine complex has close struc- 

Zinc uptake into red blood cells appears to be mediated in part by an amino acid carrier (Aiken et al. 1992). A significant fraction of plasma zinc exists complexed with amino acids, in particular, L-histidine and l-cysteine. Aiken et al. (1992) examined the role of histidine in zinc uptake by erythrocytes, and reported that transport is stimulated by L-histidine, whereas it is inhibited by D-histidine. Uptake of the L-histidine-zinc complex is Na -dependent and temperature sensitive, and is unaffected by DIDS, an inhibitor of the anion exchanger. Thus, red bloods can take up zinc as an anion (Aida Torrubia and Garay 1989), or as an amino acid complex. 

A significant fraction of plasma copper(II) is present as the L-histidine complex (CuHis2) however, this complex does not appear to be transported intact across cell membranes. Darwish et al. (1984) demonstrated that, although L-histidine enhances copper uptake by isolated rat hepatocytes, the amino acid is not cotransported with copper. The actual chemical form of 

An additional mechanism for transport of metal complexes is by endo-cytosis/exocytosis (for review see Ballatori 1991). Fluid-phase, adsorptive, and receptor-mediated endocytosis make a major contribution to the transport of metals that are bound to high molecular weight ligands, and in particular to ligands such as ferritin, transferrin, and other proteins that are selectively cleared by receptor-mediated endocytosis. Because these proteins also have some affinity for toxic metals, they may play an important role in their transport across cell membranes (Ballatori 1991). The mechanism by which metallothionein and its associated metals are removed from the circulation is not known, but the kidney appears to be the principal site of removal (Tanaka et al. 1975). When rats are injected intravenously with ° Cd-labeled metallothionein, the radioactivity is rapidly and nearly completely accumulated in the kidney (Tanaka et al. 1975). 

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