Studies on the toxicity and metabolism of cadmium-thionein

Cadmium, when bound to thionein from either rat or rabbit liver, was 7 to 8 times more toxic for the rat than was ionic Cd^{2 +}. Zinc-thionein was not only non-toxic at a dose level of 2.4 mg protein-bound-Zn^{2 +}/kg, but also protected the animals against a subsequent, normally lethal dose of cadmium-thionein. In contrast with the free cation, Cd^{2 +} administered intravenously as the metallothionein accumulated to its highest concentration in the kidney and, at a lethal dose, caused severe tubular damage. After administration of non-lethal doses of ¹⁰⁹Cd^{2 +} -labelled cadmium-thionein to rats thionein-bound-¹⁰⁹Cd^{2 +} accumulated in the kidneys, but in animals that were dosed with either the ³⁵S- or ³⁵H-labelled metalloprotein, little or none of the radioactive isotope was recovered in the renal metallothionein at 48 hr. The ³⁵S and ³H isotopes, however, were incorporated into high molecular weight proteins of the kidney soluble fraction and also were excreted in the urine, both as the metallothionein and as smaller, diffusible molecules. In vitro, ³H-labelled cadmium-thionein was degraded to acid-soluble products by homogenates of rabbit kidney cortex. It is suggested that parenterally administered cadmium-thionein is taken up by the renal tubules and catabolized, probably by the lysosomes of the tubular cells, with the liberation of Cd^{2 +} ions. These cations, if present in sufficiently high concentration, cause acute renal damage. Exposure of rats, with high hepatic concentrations of cadmium-thionein, to the hepatotoxins, carbon tetrachloride and retrorsine, did not cause the transfer of Cd^{2 +} from the liver to the kidney.