Metallothionein and Excretion of Metals

After induction of MT synthesis, the hepatic accumulation of inorganic mercury is also increased in rats. While both hepatic and renal accumulation of inorganic mercury and hepatic zinc content increased in association with zinc pretreatment, the urinary and fecal excretions of mercury were decreased (Zalups and Cherian 1992). These results support an intracellular metal-binding role for preinduced MT in the liver and kidney. The 

In Wilson s disease, where there is a defect in copper excretion pathways, high levels of MT saturated with copper are detected in the liver (Nartey et al. 1987b Danks 1989). 

A reduction in the toxicity of certain metal ions such as cadmium and mercury following induction of MT in animals has long been recognized (PiscATOR 1964). Resistance to metals has also been demonstrated in cultured cells with elevated levels of MT (Rugstard and Norseth 1975). In an earlier review, Webb (1987) discussed these effects, which were demonstrated repeatedly in various systems under different experimental conditions. However, it should be pointed out that some of these observed effects are applicable only to certain experimental conditions and may not be relevant to normal physiological conditions. 

Elevations of both glutathione and MX have been reported in mesangial cells in culture, exposed to cadmium salts (Chin and Templeton 1993). In previous comparative studies using rat liver slices, it was shown that both glutathione and MX can play a role in the protection against the cytotoxicity of cadmium and menadione (Chan and Cherian 1992 Chan et al. 1992). It was also shown that MX alone can provide an effective protective role in the acute cytotoxicity of cadmium even when the intracellular glutathione level has been significantly depleted by buthionine sulfoximine injection. 

In low-level chronic exposure, MX sequesters cadmium intracellularly as the cadmium-MT complex and thereby decreases the toxic effects of the metal. By contrast, extracellular cadmium-MX has been shown to be nephrotoxic to experimental animals. Parenteral injection of cadmium in the form of cadmium-MT can cause acute renal damage in rats and mice (Nordberg et al. 1975 Cherian et al. 1976 Squibb et al. 1984 Maitani et al. 1988). These toxic effects were similar to those observed after repeated exposure to cadmium salts but the critical renal concentration of cadmium is much lower after injection of cadmium-MX (10//g/g) than after repeated injections of cadmium salts (200//g/g). The low molecular weight cadmium-MX is freely filtered by the glomerulus and reabsorbed by the proximal convoluted tubules and can cause acute damage to the renal tubular epithelial cells (Cherian et al. 1976 Goyer et al. 1984 Dorian et al. 1992). It has been proposed that the hepatic cadmium-Mt is released and transported to kidney in blood plasma and that the nephrotoxicity occurs at a certain renal concentration of cadmium with chronic exposure (Goyer et al. 1978, 1984 Dudley et al. 1985). In a recent liver transplant experiment, the movement of cadmium-MX form liver to kidney was demonstrated in rats where the liver with cadmium-MX was transplanted to a control rat (Chan et al. 1993). 

---