Metallothionein and Cadmium Toxicology-Historical Review and Commentary

Abstract

More than one and a half centuries ago, adverse human health effects were reported after use of a cadmium-containing silver polishing agent. Long-term cadmium exposure gives rise to kidney or bone disease, reproductive toxicity and cancer in animals and humans. At present, high human exposures to cadmium occur in small-scale mining, underlining the need for preventive measures. This is particularly urgent in view of the growing demand for minerals and metals in global climate change mitigation. This review deals with a specific part of cadmium toxicology that is important for understanding when toxic effects appear and, thus, is crucial for risk assessment. The discovery of the low-molecular-weight protein metallothionein (MT) in 1957 was an important milestone because, when this protein binds cadmium, it modifies cellular cadmium toxicity. The present authors contributed evidence in the 1970s concerning cadmium binding to MT and synthesis of the protein in tissues. We showed that binding of cadmium to metallothionein in tissues prevented some toxic effects, but that metallothionein can increase the transport of cadmium to the kidneys. Special studies showed the importance of the Cd/Zn ratio in MT for expression of toxicity in the kidneys. We also developed models of cadmium toxicokinetics based on our MT-related findings. This model combined with estimates of tissue levels giving rise to toxicity, made it possible to calculate expected risks in relation to exposure. Other scientists developed these models further and international organizations have successfully used these amended models in recent publications. Our contributions in recent decades included studies in humans of MT-related biomarkers showing the importance of MT gene expression in lymphocytes and MT autoantibodies for risks of Cd-related adverse effects in cadmium-exposed population groups. In a study of the impact of zinc status on the risk of kidney dysfunction in a cadmium-exposed group, the risks were low when zinc status was good and high when zinc status was poor. The present review summarizes this evidence in a risk assessment context and calls for its application in order to improve preventive measures against adverse effects of cadmium exposures in humans and animals.

Keywords: cadmium and zinc in metallothionein; cadmium binding in blood plasma; cadmium risk assessment; cadmium toxicity; kidney toxicity of cadmium; metallothionein; metallothionein autoantibodies; metallothionein gene expression in lymphocytes; toxicokinetic model for cadmium.

Figure 1

Binding of cadmium in blood plasma. The panels show the results of gel-chromatographic (G75) separation (at +5 °C) of blood plasma from mice at various time points after s.c. injection of a single dose of radiolabeled CdCl₂. (A): 20 min after injection, (B): 96 h after injection, (C): 192 h after injection. At the shorter time (20 min) all Cd appeared in a high molecularweight peak (fractions 12–14). At longer longer times (B,C), when the concentration of Cd in plasma was 9 nanomol/kg, a considerable proportion of plasma Cd was detected in a second peak (fractions 23–24) at the molecular size of MT. Line with dots: radiocadmium, unbroken line optical density 254 nm (OD). (Picture of Original drawing of chromatographic results. Experimental details described in [27]).

Figure 2

Basic flow scheme of Cd in the body demonstrating the role of binding forms in blood and MT synthesis and degradation. aa, amino acids; Alb, albumin GSH, glutathione; MT, metallothionein. Modified from [39].

Figure 3

The relative concentrations (percent) of Cd (filled circles), Zn (open circles) and copper (black dots) in MT fractions in relation to the total MT concentration. MT isolated from the kidneys of rabbits with varying exposure to Cd [61].