Monica Nordberg

Cellular adaptation in metal toxicology and metallothionein.

The cellular adaptation to toxicity of metals is one of the important factors in the evaluation of health effects of increased exposure to metals. Two major types of cellular effects can be distinguished during divalent metal exposure. Some of the experimental evidences on the role of these processes in the cellular toxicity of metals are reviewed in this article. Both these cellular effects are somewhat specific to certain metals and involve two distinct types of protein binding. One of these processes can be considered as a nuclear process, involving binding of metals to nuclear proteins and also the formation of morphologically distinct inclusion bodies. A number of metals such as lead, bismuth, mercury, copper and aluminium are accumulated intranuclearly and bind with non-histone protein in the nuclei. In addition, morphologically distinct intranuclear inclusion bodies are formed in the kidneys of experimental animals and in humans on continuous exposure to lead or bismuth salts. Another cellular effect of divalent metals is a cytoplasmic process involving a specific metal binding protein, metallothionein. This is a unique metalloprotein containing 2 types of metal clusters and its synthesis is induced by both essential (Zn2+ and Cu2+) and non-essential (Cd2+ and Hg2+) metals. A hypothetical model for metal induced synthesis of metallothionein is postulated and is partly based on the recent immunohistochemical localization of metallothionein in the nucleus and cytoplasm of both hepatic and renal cells.

1:Metallothioneins: Historical Development and Overview

The history on research of metallothionein is reviewed. Various methods for isolation, characterization, and quantification are evaluated. The role of metallothionein in metal metabolism and toxicity is explained. Gender differences and polymorphism as well as possible relationships with diseases are discussed. The review is based on data from the literature and on own original experimental and epidemiological data. Aspects on future research within the metallothionein field are indicated.

Characterization studies on the cadmium-binding proteins from two species of New Zealand oysters.

Two different types of New Zealand oysters--Ostrea lutaria (OL) and Crassostrea glomerata (CG)--contained different concentrations of zinc, copper, and cadmium. OL oysters had 5.3 micrograms Cd/g, 3.4 micrograms Cu/g, 100 micrograms Zn/g; CG oysters had 1.4 micrograms Cd/g and 936 micrograms Zn/g. Both kinds of oysters were shown by gel filtration (G-75) to contain cadmium and zinc in fractions corresponding to a high molecular weight protein (corresponding to the size of albumin or larger) which was heat labile. OL oysters contained cadmium in fractions corresponding to a molecular weight of approximately 6500. The cadmium-binding protein in these fractions was heat-stable. This protein contained no detectable amounts of zinc and was not present in the CG oysters. Further purification by gel filtration (G-50) was performed to obtain a purer protein fraction. Isoelectric focusing of the protein obtained by G-50 filtration showed one main fraction of protein with a pI approximately 5.9 at approximately 13 degrees C. CG oysters contained cadmium and zinc in a polypeptide with low molecular weight (MW 1000). The cadmium-binding oyster proteins are minimally reactive in a competitive binding radioimmunoassay in comparison to the reactivity of a typical vertebrate metallothionein; the proteins may be metallothioneins, but, if so, they do not exhibit the principal determinants characteristic of vertebrate metallothioneins.

Comparison of tissue distribution of cadmium in mice intravenously injected with metallothionein and a polymer of metallothionein

Polymers of cadmium metallothionein I and II were prepared and used for distribution studies. Mice were intravenously injected with comparable doses of cadmium as chloride, metallothionein and metallothionein-polymer and were killed at 3 h and 24 h after injection. A considerably higher concentration of cadmium was found in the plasma and spleen of animals exposed to metallothionein-polymer than other groups, while the cadmium concentration in the kidney was less than, but in the liver was greater than those injected with cadmium-metallothionein. Gel filtration of liver and kidney cytosols showed that metallothionein is the most stable form of cadmium in the tissues. The injected polymer was degraded into the monomer within 24 h in tissues. The high concentration of polymer in plasma indicates a slow clearance of cadmium in this form. The increased antigenicity of metallothionein-polymer may be related to its slow clearance from blood and increased deposition in spleen.